TYPE Review PUBLISHED 23 February 2023 DOI 10.3389/fcell.2023.1127440 Genetic control of meiosis OPEN ACCESS surveillance mechanisms in EDITED BY Mónica Pradillo, Complutense University of Madrid, Spain mammals REVIEWED BY Bernard De Massy, Yan Huang 1,2 and Ignasi Roig 1,2* Université de Montpellier, France 1 John Schimenti, Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Cornell University, United States Barcelona, Cerdanyola del Vallès, Spain, 2Histology Unit, Department of Cell Biology, Physiology, and Karen Schindler, Immunology, Cytology, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain Rutgers, The State University of New Jersey, United States *CORRESPONDENCE Ignasi Roig, Meiosis is a specialized cell division that generates haploid gametes and is critical Ignasi.Roig@uab.cat for successful sexual reproduction. During the extended meiotic prophase I, SPECIALTY SECTION homologous chromosomes progressively pair, synapse and desynapse. These This article was submitted to Nuclear Organization and chromosomal dynamics are tightly integrated with meiotic recombination (MR), Dynamics, during which programmed DNA double-strand breaks (DSBs) are formed and a section of the journal subsequently repaired. Consequently, parental chromosome arms reciprocally Frontiers in Cell and Developmental Biology exchange, ultimately ensuring accurate homolog segregation and genetic diversity in the offspring. Surveillance mechanisms carefully monitor the MR RECEIVED 19 December 2022 ACCEPTED 10 February 2023 and homologous chromosome synapsis during meiotic prophase I to avoid PUBLISHED 23 February 2023 producing aberrant chromosomes and defective gametes. Errors in these CITATION critical processes would lead to aneuploidy and/or genetic instability. Studies Huang Y and Roig I (2023), Genetic of mutation in mouse models, coupled with advances in genomic technologies, control of meiosis surveillance lead us to more clearly understand how meiosis is controlled and how meiotic mechanisms in mammals. Front. Cell Dev. Biol. 11:1127440. errors are linked to mammalian infertility. Here, we review the genetic regulations doi: 10.3389/fcell.2023.1127440 of these major meiotic events in mice and highlight our current understanding of COPYRIGHT their surveillance mechanisms. Furthermore, we summarize meiotic prophase © 2023 Huang and Roig. This is an open- genes, the mutations that activate the surveillance system leading to meiotic access article distributed under the terms prophase arrest in mouse models, and their corresponding genetic variants of the Creative Commons Attribution License (CC BY). The use, distribution or identified in human infertile patients. Finally, we discuss their value for the reproduction in other forums is diagnosis of causes of meiosis-based infertility in humans. permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this KEYWORDS journal is cited, in accordance with meiosis, checkpoint, infertility, human infertility, mammalian accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. 1 General aspects of mammalian gametogenesis The perpetuation of most living beings and their genetic information across generations relies on a critical biological process-gametogenesis. In mammals, this process includes oogenesis and spermatogenesis, through which unipotent diploid precursor cells develop into mature haploid gametes, eggs in females, or sperm in males. After fertilization, the united egg and sperm form the embryo that develops into a new diploid organism carrying maternal and paternal genomic material. During early mouse embryonic development, primordial germ cells (PGCs) are singled out at the epiblast (at ~ embryonic day (E) 7.25) (Chiquoine, 1954; Ginsburg et al., 1990), migrate along the developing gut and eventually colonize the future gonads (at ~ E10.5) (Molyneaux et al., 2001). Soon, PGCs switch from multipotential to bipotential and obtain the competence to initiate sexual differentiation and meiosis (Lesch and Page, 2012). At ~ E12.5, the expression of the Y chromosome-encoded gene, Sry, determine the gonads to become the testes (Koopman et al., 1991). Consequently, PGCs commit to divergent Frontiers in Cell and Developmental Biology 01 frontiersin.org Huang and Roig 10.3389/fcell.2023.1127440 development based on the cues from the somatic environment: Russell, 2000; Oatley and Brinster, 2008). Spermatogenesis female and male PGCs differentiate to their specialized gamete continues with the mitotic expansion of spermatogonia, the precursors: oogonia and spermatogonia, which initiate meiosis to meiotic divisions of spermatocytes, and the morphological form eggs through oogenesis or sperm through spermatogenesis transformations of spermatids. (Edson et al., 2009). SSCs are testis-specific stem cells derived from PGCs. In mice, In mammals, meiosis exhibits substantial sexual dimorphism male PGCs arrested at the G0/G1 phase migrate and differentiate (Handel and Eppig, 1997; Morelli and Cohen, 2005). Female meiosis into SSCs around 3 days postpartum (dpp) (Bellve et al., 1977; is initiated roughly simultaneously in all oogonia during fetal McLean et al., 2003). One subpopulation of these cells development and subsequently arrests at the end of meiotic (Neurogenin 3 (NGN3)-negative) initiates the first round of prophase I (dictyotene stage) around birth. It resumes producing spermatogenesis during the second week after birth; the other eggs periodically after puberty over a defined reproductive lifetime. subpopulation develops into morphologically distinct, NGN3- Female meiosis I does not complete until ovulation, and meiosis II positiveSSCs and supplies SSCs for spermatogenesis during only occurs under the trigger of fertilization, eventually generating adulthood (Yoshida et al., 2006). SSCs (As (A-single) only one haploid oocyte from one oogonium. In contrast, male spermatogonia) undergo symmetric division to produce SSCs for meiosis is initiated in separate cohorts of spermatogonia after the self-renewal or progenitor spermatogonia (Apr (A-paired) onset of puberty and provides continuous sperm production spermatogonia) for differentiation, which marks the beginning of throughout most of adult life. The two meiotic cell divisions in spermatogenesis. SSC self-renewal predominates during the males are consecutive and result in four haploid sperm from each neonatal period to establish a stem cell pool (Shinohara et al., spermatogonium that initiates meiosis. 2001) but only occurs periodically under steady-state conditions Both spermatogonia and oogonia enter meiosis during during adulthood to maintain the SCC pool (Oatley and Brinster, preleptotenema but before S phase. The sexually dimorphic 2012). Apr spermatogonia undergo seven rounds of mitotic cell timing of meiosis entry depends on the Stimulated by Retinoic divisions to form undifferentiated Aal spermatogonia (Aal Acid gene 8 gene (Stra8) (Handel and Schimenti, 2010). In females, (A-aligned) spermatogonia)and differentiated A1, A2, A3, A4, In retinoic acid (RA) synthesized in the mesonephric ducts (Bowles (Intermediate), and B spermatogonia. B spermatogonia differentiate et al., 2006) induces Stra8 expression, resulting in meiosis initiation into preleptotene spermatocytes via a final round of mitosis and (Koubova et al., 2006; Baltus et al., 2006); however, in males, RA is initiate meiosis (Russell et al., 1993; de Rooij and Russell, 2000; Rato degraded by CYP26B1 (gene cytochrome P450, family 26, subfamily et al., 2012). b, polypeptide 1) from Sertoli cells, preventing the induction of Diploid spermatocytes proceed through meiosis, resulting in Stra8 and thus blocking the meiotic entry (Bowles et al., 2006). The haploid round spermatids. Subsequently, these round spermatids ability to enter meiosis is gained in males postnatally when the undergo structural and functional changes, including nuclear expression of CYP26B1 is repressed in male gonads (Koubova et al., remodeling by chromatin condensation, removing the excess 2006; Bowles et al., 2006; Anderson et al., 2008; Lesch and Page, cytoplasm, and forming an acrosome and a sperm tail 2012). The exact RA-Stra8 meiotic initiation pathway remains (spermiogenesis) (Hermo et al., 2010; Lehti and Sironen, 2016). elusive. This is mainly due to the role of RA as a meiosis- As a result, spermatids become motile spermatozoa and are released inducing substance is unclear and has been challenged (Kumar to the central seminiferous lumen (spermiation). Spermatozoa will et al., 2011; Vernet et al., 2020), particularly by a recent study complete the final maturation to become fertilizable sperm in the showing that meiosis can normally occur in the absence of all RA epididymis. receptors in female mice (Vernet et al., 2020). The role of STRA8 in Spermatogenesis occurs within the seminiferous tubules of the meiotic initiation is more clear and STRA8 is suggested recently to testis, in which germ cells in different stages of development are trigger meiosis initiation in mice together with MEIOSIN in a broad organized into a series of cell associations known as stages. In mouse transcriptional network, probably by activating genes responsible for testis, 12 stages have been defined (Hasegawa and Saga, 2012). RA suppressing the mitotic program and establishing a meiosis-specific pulses progressively stagger along the tubule and stimulate the chromosome structure under the presence of RA (Kojima et al., spermatogonia to enter the rigidly timed pathway committed to 2019; Ishiguro et al., 2020). Notably, other pathways are also meiosis. This determines the seminiferous epithelial cycle initiation suggested to mediate meiosis initiation in mice, such as the and eventually enables the continuous release of spermatozoa (de BMP-ZGLP1 pathway that works in parallel with RA-STRA8 Rooij and Russell, 2000). signaling (Nagaoka et al., 2020), STRA8-independent RA-REC8 In the seminiferous epithelium, Sertoli cells form specialized pathway (Koubova et al., 2014; Soh et al., 2015) and epigenetic tight junctions (so-called “blood-testis barrier” (BTB)) at their base regulated negative controls (Yamaguchi et al., 2012; Yokobayashi to separate the seminiferous epithelium into basal (where the et al., 2013; Endoh et al., 2017). spermatogonial population resides) and the adluminal compartments (where the meiotic and haploid germ cells reside). The BTB blocks the elements from the interstitial space to maintain 1.1 Spermatogenesis homeostasis for meiotic and haploid germ cell development in the adluminal compartment (O’Donnell et al., 2000; Oatley and Mammalian male fertility requires millions of sperm produced Brinster, 2008). The BTB remodels periodically (controlled by daily by continuous spermatogenesis throughout reproductive life. RA) to ensure preleptotene spermatocytes enter the adluminal The continual spermatogenesis is founded on a stem cell pool compartment to initiate meiosis (Hasegawa and Saga, 2012). The supplied by spermatogonial stem cells (SSCs) (de Rooij and steroidogenic Leydig cells reside in interstitial tissue between the Frontiers in Cell and Developmental Biology 02 frontiersin.org Huang and Roig 10.3389/fcell.2023.1127440 seminiferous tubules and secrete testosterone under the influence dorsal region of the mouse ovary is activated to grow during the first of LH. week of postnatal development, the first wave of folliculogenesis (Cordeiro et al., 2015). After puberty, quiescent primordial follicles are continually recruited through primordial activation to initiate 1.2 Oogenesis follicular development, forming primary follicles with a single layer of cuboidal granulosa cells (Lintern-Moore and Moore, 1979). Mammalian oogenesis begins during embryonic development Primary follicles continue developing through two phases: pre- and generates primary oocytes assembled in primordial follicles antral and antral phases. Through the pre-antral phase, primary perinatally. The establishment of the pool of primordial follicles follicles become secondary/pre-antral follicles with two or more determines mammalian female fertility. Post-pubertally, primordial layers of granulosa cells. This development is independent of follicles are recruited irreversibly and develop into mature follicles gonadotropins and is mainly regulated by autocrine and during the estrous/menstrual cycle, eventually releasing mature and paracrine signaling, specifically, the TGF-β family members such fertilizable oocytes. As a result, the ovarian reserve is gradually as oocyte-secreted GDF-9 and BMP-15 (Yan et al., 2001; reduced, defining a finite female reproductive life span (Kerr et al., Günesdogan and Surani, 2016; Namwanje and Brown, 2016). 2013; Li and Albertini, 2013; Wear et al., 2016; Hunter, 2017; Ruth Through the antral phase, antral follicles are formed. The et al., 2021). presence of an antrum-a granulosa cell-secreted fluid-filled cavity In mice, after differentiation of PGCs, oogonia undergo mitotic characterizes antral follicles. The follicle development during this divisions with incomplete cytokinesis, forming germ cell cysts in phase depends on gonadotropins FSH and LH (Williams and which daughter cells are connected by intercellular bridges Erickson, 2000). FSH stimulates granulosa cells to proliferate and (McLaren and Monk, 1981; Pepling and Spradling, 1998). On secrete estrogens. LH stimulates the theca cells to produce E13.5, oogonia in the cysts initiate meiosis and eventually progesterone and testosterone. More importantly, the rise of the differentiate into primary oocytes, which will complete the first FSH level during the menstrual cycle allows the selection of meiotic prophase and arrest at dictyotene perinatally (Borum, 1961). dominant follicles, enabling only some of the growing antral After cyst breakdown, primary oocytes are enclosed in a layer of follicles to develop into ovulatory follicles (Zeleznik, 2004). somatic pre-granulosa cells, forming primordial follicles by 4dpp Since the initiation of follicular development, oocytes start to (Pepling and Spradling, 2001). The formation of primordial follicles grow in size and are transcriptionally and translationally active is a complex process. It requires the presence of germ cells (Lintern-Moore and Moore, 1979). However, they remain arrested (McLaren, 1984) and involves communication between oocytes at the end of the meiotic prophase, marked by a large nucleus-the and pre-granulosa cells (Pepling, 2012). germinal vesicle-with a prominent nucleolus. This arrest is In mammals, massive oocyte culling accompanies oogenesis. maintained by the combined effects of the cyclic adenosine Mouse oocyte numbers begin to decline since E14.5, remain about monophosphate (cAMP) and cyclic guanosine monophosphate half at birth, and continue reducing postnatally. At 4dpp, eventually, (cGMP) (Norris et al., 2009; Jaffe and Egbert, 2017). When the only 20% of fetal oocytes remain in the ovaries (Malki et al., 2014; follicles reach the preovulatory stage, in response to LH surge, Hunter, 2017; Martínez-Marchal et al., 2020). This massive oocyte oocytes will resume meiosis and complete maturation, as seen by death might result from oocyte quality control (Hunter, 2017). the germinal vesicle breakdown. Subsequently, oocytes complete the Oocytes with potential defects due to the activation of first meiotic division but arrest at metaphase II upon ovulation and LINE1 transposon are eliminated during embryonic development will resume meiosis if fertilized, eventually generating a mature (E15.5-18.5) in mice, leaving only oocytes with limited oocyte with two or three polar bodies that will undergo apoptosis. LINE1 activity (Malki et al., 2014). Postnatally, oocyte culling Besides the nuclear maturation, which involves the haploidization of occurs in response to errors in meiotic prophase I to remove the genome, the oocyte cytoplasm must also mature through major oocytes that might have chromosomal defects (Di Giacomo et al., translational, post-translational, and organellar modifications, 2005). Additionally, the loss of oocytes is also suggested to be the which are essential for the completion of meiosis, fertilization, self-sacrifice of the so-called nursing oocytes, similarly to a well- and early embryonic development (reviewed in Li and Albertini, characterized process that occurs during oogenesis in Drosophila 2013). (Lei and Spradling, 2016). In Drosophila, during oogenesis, nurse cells surrounding the growing oocyte provide nutrients and other factors required for development. The nurse cells form a syncytium 2 Meiosis with the egg, where the cytoplasm and organelles are shared among the cells, allowing for efficient transport of substances to the growing Meiosis is a specialized cell division critical for gametogenesis in egg. Additionally, the nurse cells also help to regulate the all sexually reproducing organisms. Through meiosis, a diploid developmental program of the egg by providing signals and parental cell gives rise to haploid daughter cells, and this is controlling the expression of specific genes. In this way, the achieved by a single round of DNA replication followed by two nursing cells play a crucial role in ensuring the proper rounds of cell divisions (Kleckner, 1996). Homologous development and survival of the egg. Thus, the oocyte quality chromosomes separate during the first division (meiosis I), and control processes select the most suitable oocytes for the next- sister chromatids separate during the second division (meiosis II) generation. analogously to mitosis, resulting in the generation of haploid cells. A Newly formed primordial follicles remain quiescent until canonical meiotic program present in most organisms (e.g., recruited. A cohort of primordial follicles located at the anterior- mammals, budding yeast, plants, etc.) will be briefly described in Frontiers in Cell and Developmental Biology 03 frontiersin.org Huang and Roig 10.3389/fcell.2023.1127440 FIGURE 1 Meiotic prophase I overview. This schematic illustrates chromosome dynamics during meiotic prophase I in spermatocytes and oocytes (left panel) and the meiotic recombination pathway (right panel). Left panel, in meiotic prophase I, each paternal (black) or maternal (grey) homologous chromosome is organized around a chromosomal axis. During leptonema, axial elements (AEs) develop for each chromosome, and programmed SPO11-induced DSBs are generated as recombination initiates. During zygonema, synapsis initiates between paired homologs. Then it spreads along with the entire AEs as the SC central region (CR) proteins (consisting of the transverse filaments (TFs) and the central element (CE)) are installed between the AE. AEs are then designated as lateral elements (LEs) of the SC. In the meantime, DSBs are gradually repaired as recombination progresses. By pachynema, homologous chromosomes are fully synapsed, except for the heteromorphic X and Y chromosomes in the spermatocytes, which synapse only in a short pseudoautosomal region and form a transcriptionally silent chromatin compartment known as the sex body. By the end of pachynema in spermatocytes or during late pachynema/early diplonema in oocytes, meiotic recombination completes as DSBs on autosomes are all repaired, and crossovers (COs) are generated. During diplonema, the CR is disassembled, and homologous chromosomes are only held together at the CO sites (chiasmata). From diplonema, spermatocytes progress to metaphase I, completing meiotic divisions without interruption. In contrast, oocytes arrest at the dictyate stage until meiotic resumption after puberty. Right panel, several major events and critical transitions occur during meiotic recombination. Mammalian proteins that are, or are predicted (underlined) to be, involved in each event are listed. SPO11 catalyzes DSB formation in association with its accessory proteins. DSB ends are further resected through a series of nucleolytic activities mediated by the MRN complex (MRE11- RAD50-NBS1) and others. As a result, a short oligonucleotide covalently attached to SPO11 (SPO11 oligo) is released, and 3′ ssDNA tails are generated, which are immediately coated by ssDNA binding proteins (such as RPA, MEIOB, SPATA22, etc.). Recombinases DMC1 and RAD51 assemble at resected 3’ ssDNA tails, promoted by recombination proteins such as MEILB2, BRCA2, BRME1, etc. RAD51 and DMC1 coated ssDNA are stabilized by HOP2-MND1 and engage in homology search and strand exchange, resulting in D-loop formation. The repair can proceed by either a double Holliday junction (dHJ) pathway or synthesis-dependent strand annealing (SDSA). ZMM proteins and other factors control this by processing and stabilizing the recombination intermediates. In the dHJ pathway, D-loops are further stabilized by MutSγ homologs (MSH4 and MSH5), and the second end of the DSB is captured to form a dHJ, requiring RPA-MEIOB- SPTATA22 complex. ZMM proteins such as HEI10 and RNF212 facilitate the recruitment of mismatch repair factors MutLβ homologs (MLH1, MLH3). MutLβ and EXO1 mediate the resolution of dHJ, primarily giving rise to crossover (CO) products. In SDSA, the invading strand is displaced after DNA synthesis and reanneals to the other end of the DSB, followed by further DNA synthesis and nick ligation, ultimately giving rise to non-crossover (NCO) products. this section and expanded in detail, focusing on the two major subsequently bound by the RecA family of strand exchange proteins meiotic events, synapsis and meiotic recombination (MR), in the (DMC1, RAD51) (San Filippo et al., 2008). This protein following sections. Findings in mice will be prioritized to discuss in nucleofilament searches and invades homologous repair line with the scope of this review. However, data from other species, templates, initiating the repair pathways to form crossovers particularly yeast, will be addressed whenever necessary or of (COs), with reciprocal exchange of chromosome arms flanking interest. the DSB site, or non-crossovers (NCOs), with no exchange of Meiosis is characterized by an extended prophase I, during flanking parental sequences (Keeney and Neale, 2006; Hunter, which MR occurs (Figure 1). MR initiates in early prophase I 2015). NCOs promote homolog pairing while COs establish the with the formation of numerous DNA double-strand breaks connections between homologous chromosomes to ensure accurate (DSBs) catalyzed by the conserved SPO11 protein (Keeney, segregation at meiosis I and reshuffle parental alleles to increase 2001). DSB ends undergo resection and generate 3′ssDNA ends, genetic diversity in offspring (Hunter, 2015; Lam and Keeney, 2015). Frontiers in Cell and Developmental Biology 04 frontiersin.org Huang and Roig 10.3389/fcell.2023.1127440 MR is tightly integrated with a highly-organized and dynamic chromosomal events during the meiotic prophase I will also be chromosome structure throughout the five substages of meiotic presented in the following sections whenever necessary. prophase I (leptonema, zygonema, pachynema, diplonema, and diakinesis) (Zickler and Kleckner, 1999). During leptonema, the chromatin condenses at the developing chromosomal axes, and 2.1 The synaptonemal complex and synapsis recombination initiates. The axes provide a rod-like center for the loops of every pair of chromatids to anchor, defining a loop- The SC is a highly conserved meiosis-specific feature. This is axis structure essential for DSB formation and repair template likely attributed to a conserved SC organization, e.g., the coiled-coil choice (Subramanian and Hochwagen, 2014). During zygonema, domains (Gao and Colaiácovo, 2018), whereas its component maternal and paternal homologs progressively pair. The loop-axis proteins share little similarity at the amino acid sequence level organization makes this close alignment of homolog axes possible. (Grishaeva and Bogdanov, 2014; Fraune et al., 2016). The SC However, understanding how base-pair resolution pairing is serves as the scaffold for the close juxtaposition of homologous achieved in the context of the complex meiotic chromosome chromosomes and is intimately associated with chromosome architecture is limited. Several regulation layers, including meiotic pairing, synapsis, and recombination (Fraune et al., 2012; recombination and dynamic chromosome movement, are suggested Cahoon and Hawley, 2016; Geisinger and Benavente, 2017; Gao to promote homolog pairing (Bolcun-Filas and Handel, 2018). and Colaiácovo, 2018). Fully formed SC is revealed as a tripartite Synapsis initiates as a tripartite proteinaceous scaffold–the structure by electron microscopy, consisting of two LEs that run synaptonemal complex (SC)- which starts to form between the along the electron-dense chromatin and flank a CR (Moses, 1969), paired homologous chromosome axes to create an intimate composed of a central element (CE) and numerous transverse association between them. While in some organisms (e.g., filaments (TFs). In mammals, eight meiotic-specific SC proteins Neurospora, and Coprinus), synapsis initiates only after all have been identified and characterized so far (Schücker et al., 2018): homologs complete pairing, in budding yeast and mammals, SYCP2 and SYCP3 as the LE proteins (Lammers et al., 1994; synapsis begins concomitantly with homolog pairing at Offenberg et al., 1998); SYCP1 as the TF protein (Meuwissen zygonema. The telomeres and several interstitial sites of DSB- et al., 1992), and SYCE1, SYCE2, SYCE3, TEX12, and mediated inter-homolog associations are often where synapsis SIX6OS1 as the CE proteins (Costa et al., 2005; Hamer et al., initiates (Fung et al., 2004), while in mice and several organisms 2006; Schramm et al., 2011; Gómez-H et al., 2016). with metacentric chromosomes, including humans, centromeres are The SC plays a universal role, as providing order within the often the last to synapse (Roig et al., 2010; Bisig et al., 2012; Qiao nucleus during prophase, in all species. But it may also have diverse et al., 2012). Once it initiates, synapsis quickly spreads along the roles in many organisms. Notably, it is essential for multiple steps chromosomes in both directions in a zipper-like manner. At during MR (Zickler and Kleckner, 2015). The SC regulates pachynema, the SC is fully installed along the entire length of all programmed DSB formation as synapsis shuts off the homologous chromosomes (Fraune et al., 2012). The last SPO11 activity (Kauppi et al., 2013). The AE proteins are closely recombination steps after strand invasion occur in the SC associated with the development of recombination protein context, which further helps keep the homologs in association, complexes. The CR plays a significant structural role in these generating COs at the end of pachynema. Subsequently, the SC complexes’ assembly, maintenance, and turnover, thereby disassembles asymmetrically between homologs throughout enabling the maturation of the DSBs into COs subject to diplonema and diakinesis, accompanied by changes in interference. In mice, recombination can not be completed chromosome compaction (Gao and Colaiácovo, 2018). By late without the CR proteins (Bolcun-Filas et al., 2007; Schramm diakinesis, the highly condensed bivalents only remain connected et al., 2011; Fraune et al., 2012; Gómez-H et al., 2016). Moreover, by chiasmata, the cytological manifestation of COs. These inter- the SC is responsible for holding homologs after the repair of NCO- homologous connections ensure correct segregation under tension fated DSBs and maintaining interhomolog interactions until COs by allowing homolog pairs to stably bi-orient at the metaphase I are formed (Zickler and Kleckner, 1999; Qiao et al., 2012). Finally, spindle (Handel and Schimenti, 2010). As Meiosis I completes, the SC might be centrally important in the surveillance of meiotic maternal and paternal chromosomes are separated into daughter recombination and HORMAD-regulated monitoring of synapsis. cells. Then in Meiosis II, sister chromatids separate, ensured by their The SC undergoes a dynamic cycle through its assembly, a centromeric cohesion, resulting in the generation of haploid cells highly dynamic steady-state, and disassembly (Gao and Colaiácovo, (Ishiguro, 2019). 2018). Its assembly is through integrating the CR proteins to connect Meiosis must be carefully monitored to preserve the order of two LEs, a poorly understood process that might differ in various meiotic events and avoid producing aberrant chromosomes and organisms due to the divergent SC component proteins (Cahoon defective gametes (Subramanian and Hochwagen, 2014). In mice, and Hawley, 2016). surveillance mechanisms monitor recombination and synapsis at the In mice, a picture of how the SC proteins are assembled in order pachytene stage (meiotic checkpoint) (Roeder, 2000) and control has been inferred from mouse knockout studies (Fraune et al., 2012; bipolar attachment to the spindle at metaphase I (the spindle Geisinger and Benavente, 2017). After DNA replication in the pre- assembly checkpoint, SAC) (Touati and Wassmann, 2016). meiotic S-phase, each pair of sister chromatids are tightly held Recent mice findings have revealed new mechanistic insights on together by cohesin complexes. The chromatin of sister chromatids how meiotic checkpoints monitor these meiotic prophase events in is organized in a linear array of loops emanating from the mammals, which will be mainly discussed below. The roles of the chromosome axis, forming the meiotic axis-loop organization, meiotic checkpoint machinery in preserving the order of which allows the close juxtaposition of homolog axes during Frontiers in Cell and Developmental Biology 05 frontiersin.org Huang and Roig 10.3389/fcell.2023.1127440 meiotic prophase (Zickler and Kleckner, 2015). During preleptotene In mice, AE formation depends on meiotic cohesion with stage, the AE/LE proteins: SYCP2 and SYCP3 load onto the cohesin different contributions from different cohesin (reviewed in complex together with the HORMA domain-containing proteins (Ishiguro, 2019). HORMAD1 is essential for both homolog (HORMAD1 and HORMAD2) (Wojtasz et al., 2009), forming the pairing and synapsis (Shin et al., 2010; Kogo et al., 2012a; Paigen chromosome axis during meiotic prophase I (Zickler and Kleckner, and Petkov, 2018) as HORMAD1 promotes efficient DSB formation 1999; Yuan et al., 2000; Yang et al., 2006; Fujiwara et al., 2020). and enables DSB-mediated homology search (Shin et al., 2010; Kogo Recent studies suggest that SYCP2 mediates the anchoring of et al., 2012a; Paigen and Petkov, 2018). Moreover, chromatin loops to the axis by associating with the cohesin HORMAD1 might also have a direct role in SC formation complex (Feng et al., 2017; Xu et al., 2019). Moreover, (Paigen and Petkov, 2018). Additionally, both HORMAD1 and SYCP2 possesses putative ‘closure motifs’ that might be HORMAD2 are required to surveil homolog synapsis (Wojtasz responsible for HORMADs recruitment (West et al., 2019). Then, et al., 2009; Kogo et al., 2012b; Paigen and Petkov, 2018). Their the CR proteins: SYCP1, SYCE3, and SYCE1, which are essential for absence rescues the loss of asynaptic oocytes in the SPO11-deficient synapsis initiation, are assembled between the AEs in sequence: the background (details below). TF protein SYCP1 first associates with the AEs, likely through In yeast, synapsis initiation is controlled by the ‘ZMM’ proteins. interacting with SYCP2 (Winkel et al., 2009; Schücker et al., Also, the SUMOylation of several SC components is required for SC 2015); and then recruits SYCE3 through direct interaction assembly (Humphryes et al., 2013; Leung et al., 2015). In mice, SC (Schramm et al., 2011; Hernández-Hernández et al., 2016). initiation depends on the total number of interhomolog Subsequently, SYCE1 is loaded likely through interacting with engagements. Reduced DSBs levels lead to fewer interhomolog SYCE3 (Lu et al., 2014). SYCE1 also interacts with and stabilizes engagements, causing delayed synapsis (Kauppi et al., 2013). SYCP1 (Costa et al., 2005). Recently, a novel CE protein, SIX6OS1, Whether SUMOylation is involved in SC assembly in mice is has been shown to be required downstream of SYCP1 at a similar unclear, although similar to yeast Red1, mouse SYCP3 can also hierarchy level to SYCE3 (Gómez -H et al., 2016b). Finally, synapsis be SUMOylated (Xiao et al., 2016). A positive feedback system in spread along the entire length of homolog axes with the required yeast controls SC polymerization. The initial assembly of the loading of SYCE2 and TEX12 (Hamer et al., 2006). These proteins transverse filament recruits central-element proteins, which interact with the SC through SYCE2 binding to SYCP1, SYCE3, and recruit more transverse filaments. The mechanism controlling SC SYCE1 (Costa et al., 2005; Bolcun-Filas et al., 2007; Schramm et al., polymerization in mice remains unknown (Cahoon and Hawley, 2011) and interact interdependently to promote the assembly and 2016). The control of the timing between the formation of a CO and stabilization of the SC (Cahoon and Hawley, 2016; Geisinger and SC disassembly is vital for proper chromosome segregation. In mice, Benavente, 2017). All these CR proteins are required for fertility in this relies on cell-cycle kinases (PLK1, Aurora B, CDK1-Cyclin B1), female and male mice, unlike LE proteins, whereas knockout which are regulated through transcriptional and translational SYCP2 or SYCP3 leads to sterility in males but subfertility in mechanisms (Gao and Colaiácovo, 2018). females (Yang et al., 2006; Bolcun-Filas et al., 2007; Gómez-H et al., 2016). The SC is completely assembled between all the lengthwise- 2.2 Meiotic recombination aligned homologs at the pachytene stage. Interestingly, this SC structure is highly dynamic during early pachytene in yeast and Meiotic recombination is homologous recombination (HR)- C. elegans as the SC subunit composition are constantly changing where the homologous chromosomes are used as the template (Voelkel-Meiman et al., 2012; Pattabiraman et al., 2017) and shifts to for DSB repair, generating NCO and CO products and impacting a more stable state in late pachytene as recombination progresses. several other meiotic events during meiosis (Keeney, 2008; Lam and After CO formation, the SC disassembles as SYCP1 is lost from Keeney, 2015). In many organisms, including mammals, MR chromosome arms in diplotene. However, SC fragments remain at promotes the close juxtaposition of each pair of homologous centromeres and CO sites, presumably to coordinate local chromosomes, thus facilitating chromosome synapsis. DSB- chromosome organization and separate the homologous axes, mediated interhomolog interactions generate CO products in the until diakinesis (Bisig et al., 2012; Qiao et al., 2012). After context of synapsed chromosomes, resulting in the exchange of removing SYCP1 from the centromeres, SYCP3 accumulates and alleles between homologs. Besides, COs facilitate the proper persists in these regions until late diplotene, before the nuclear- orientation of homologous pairs at metaphase and thus ensure envelope breakdown, likely to promote proper homologous they segregate accurately at the first meiotic division, eventually centromere bi-orientation, ensuring appropriate homolog supporting functional gametes formation (Hunter, 2015; Lam and segregation (Bisig et al., 2012; Qiao et al., 2012). Keeney, 2015; Marsolier-Kergoat et al., 2018) (Figure 1). Multiple layers of regulation are imposed on the formation and MR initiates when numerous programmed DSBs are induced by disassembly of the SC to coordinate these mechanisms with the MR the conserved SPO11 protein, the ortholog of subunit A of TopoVI in various organisms (Zickler and Kleckner, 2015; Gao and DNA topoisomerase (TopoVIA) (Bergerat et al., 1997; Keeney et al., Colaiácovo, 2018). These include the regulation from structural 1997). It catalyzes DNA cleavage via a transesterification reaction, axial protein (cohesin and HORMADs), the transcriptional generating meiotic DSBs covalently bound by SPO11 at the 5′end regulation of the SC genes, translational control of SC proteins (De Massy et al., 1995; Liu et al., 1995) (Figures 1–5). mRNAs, the association of non-structural regulators with SC In many organisms, accessory DSB proteins are also required for components, protein modifications, etc. (Zickler and Kleckner, SPO11-mediated DSB formation (Lam and Keeney, 2015). Notably, 2015; Gao and Colaiácovo, 2018). a TopoVIB-like subunit (TOPOVIBL), structurally similar to the Frontiers in Cell and Developmental Biology 06 frontiersin.org Huang and Roig 10.3389/fcell.2023.1127440 TopoVIB subunit of Topo VI topoisomerase, is also essential for et al., 2015; Lukaszewicz et al., 2021). Besides, ATM might be meiotic DSB formation in mice and most likely in most eukaryotic involved in other feedback circuits to ensure enough DSBs are species (Robert et al., 2016; Vrielynck et al., 2016). formed to support homolog interactions and recombination In budding yeast, nine other accessory proteins form different (Cooper et al., 2014). subcomplexes, directly or indirectly interacting with SPO11, and are After DSB formation, DSB ends are resected to generate ssDNA all required for DSB formation, including Ski8, Rec102-Rec104 tails (Baudat et al., 2013; Lam and Keeney, 2015) (Figure 1). complex, Rec114-Mei4-Mer2 complex, Mre11–Rad50–Xrs2 The DSB resection is well elucidated in budding yeast. The MRX (MRX) complex (Lam and Keeney, 2015; Yadav and Claeys complex recognizes DNA-bound Spo11 and generates nicks nearby Bouuaert, 2021). In mice, three evolutionarily conserved proteins with Sae2, leading to the release of Spo11 bound to short have also been identified to be required for SPO11-mediated DSB oligonucleotides (Spo11 oligos) (Neale et al., 2005; Cannavo and formation, including IHO1, MEI4, and REC114, the mouse Cejka, 2014). The nicks serve as entry points for short-range orthologs of yeast Mer2, Mei4, and Rec114, respectively. These 3′→5′resection, mediated by Mre11 exonuclease activity, and three proteins colocalize on the axes of the meiotic chromosome long-range 5′→3′resection, mediated by Exo1 exonuclease independently of SPO11 activity (Kumar et al., 2010; Stanzione et al., activity and Dna2 nuclease (Manfrini et al., 2010; Zakharyevich 2016; Kumar et al., 2018). et al., 2010; Garcia et al., 2011). The consequence is the generation of IHO1 is a direct interactor of the axial component protein 3′ssDNA tails on both sides of the DSB. The full-length resection HORMAD1 in mice (Stanzione et al., 2016). It is required for the requires the DSB-responsive kinase Tel1, which promotes resection axis-localization of REC114 and MEI4 in vivo. However, its axial initiation, likely through Sae2 phosphorylation (Cartagena-Lirola localization is independent of MEI4 or REC114. Thus, IHO1 might et al., 2008), and regulates resection length (Mimitou et al., 2017). act as a platform to recruit REC114 and MEI4 to the axes (Stanzione In mammals, EXO1 is dispensable for DSB resection (Wei et al., et al., 2016; Kumar et al., 2018). REC114 directly interacts with 2003), and the nucleotide-excision repair factor, DNA polymerase- TOPOVIBL in mice, regulating the SPO11/TOPOVIBL catalytic β, is implicated in SPO11 removal (Kidane et al., 2010). However, activity (Nore et al., 2022). It is also inferred to perform this function the role of the mammalian MRX complex and Sae2 homologs, the via ATM-dependent inhibition of DSBs (Subramanian and MRN complex (MRE11-RAD50-NBS1) and CtIP, respectively, in Hochwagen, 2014; Boekhout et al., 2019). ATM might target meiotic DSB repair is poorly understood due to the embryonic REC114 directly by phosphorylating it, as in S. cerevisiae lethality of knocked-out mice of any MRN component (Pacheco (Carballo et al., 2013), or indirectly by phosphorylating et al., 2015; Zhang et al., 2020a). A recent study has demonstrated ANKRD31, a novel interactor of REC114 (Boekhout et al., 2019; that conditional disruption of NBS1 in mouse testis causes a Papanikos et al., 2019). dramatic reduction of DNA end resection and severe defect in DSBs are non-randomly distributed along the chromosomes. chromosome synapsis, eventually leading to meiotic arrest and They tend to accumulate preferentially at regions called infertility (Zhang et al., 2020a). Thus, like MRX in yeast, the recombination hot spots (Székvölgyi et al., 2015), which are MRN complex is likely essential for mammalian DSB resection. determined by PRDM9 in most mammals (Paigen and Petkov, Resected 3′ssDNA tails are immediately bound by replication 2018). PRDM9 binds to specific DNA sequences in the genome protein A (RPA) and RPA1-related protein MEIOB and its through its zinc finger array. It then methylates histone H3 lysines associated factor, SPATA22. The recombinases DMC1 and 4 and 36 (H3K4me3 and H3K36me3) of nearby nucleosomes using RAD51 further replace these. Then, one of the RAD51/DMC1- its PR/SET domain, activating hot spots (Grey et al., 2018). Activated coated ssDNA commences engaging in homology search and hot spots are believed to mainly locate at the DNA loops. It is not interhomolog interactions. Consequently, unstable nascent fully understood how they are further associated with the D-loop intermediates are likely generated in vivo. These are chromosomal axis where SPO11 and the accessory proteins are either destabilized in the NCO pathway or stabilized in the CO located. Studies have speculated that EWSR1, CDYL, EHMT2, and pathway (Brown and Bishop, 2015; Hunter, 2015) (Figure 1). CXXC1 proteins might mediate this association through binding the DMC1 and RAD51 are strand-exchange proteins. KRAB domain of PRDM9 and interacting with the DSB proteins RAD51 functions in somatic and meiotic cell cycles, whereas (Imai et al., 2017; Parvanov et al., 2017). As a result, PRDM9 targets DMC1 is meiosis-specific (Brown and Bishop, 2015). DMC1 is SPO11 to specific genome regions, generating DSBs. Nevertheless, the essential DNA strand–exchange factor in meiosis, while some DSB sites are targeted independently of PRDM9 in meiosis, RAD51 could be dispensable but performs a critical regulatory e.g., the pseudoautosomal region (PAR) in male meiosis (Brick et al., role in yeast and mammals (Cloud et al., 2012; Hinch et al., 2020). 2012). The assembly of both recombinases is ATP-dependent and DSB formation is tightly controlled to occur in a narrow time promoted by several recombination factors in mammals such as window within prophase I, and in yeast, ATM plays an essential role ATR, breast cancer 2 protein (BRCA2), TRIP13, the Shu complex in this by regulating further DSB formation via a negative feedback SWS1-SWSAP1, and PALB2, etc. (Zelensky, Kanaar, and Wyman, loop both in trans and cis (Barchi et al., 2008; Lange et al., 2011; 2014; Abreu et al., 2018; Roig et al., 2010; Pacheco et al., 2018; Felipe- Zhang et al., 2011; Garcia et al., 2015; Pacheco et al., 2015). Depleting Medina et al., 2020; Zhang et al., 2020b; Zhang et al., 2019a; Widger ATM leads to significantly increased DSBs in multiple organisms, et al., 2018). Several recent studies identified BRCA2 localizer including mice (Joyce et al., 2011; Lange et al., 2011; Kurzbauer et al., (MEILB2) and MEILB2’s stabilizer (BRME1), both of which form 2012; Pacheco et al., 2015). ATM might prevent repeated DSB a complex with BRCA2 and function as the recruiter of RAD51 and formation at the same chromosomal locus in mice as in yeast (La DMC1 onto ssDNA (Zhang et al., 2019a; 2020b; Felipe-Medina Salle and Trasler, 2006; Barchi et al., 2008; Lange et al., 2011; Garcia et al., 2020). The activity of the DMC1-RAD51 complex to promote Frontiers in Cell and Developmental Biology 07 frontiersin.org Huang and Roig 10.3389/fcell.2023.1127440 homology search and strand exchange is driven by the stability of the repair and form the MutSγ heterodimer (Pochart et al., 1997), which formed nucleoprotein filament (Brown and Bishop, 2015), which is is essential for chromosome synapsis, CO formation, and thus enhanced by the HOP2-MND1 complex (Petukhova et al., 2003; fertility in mice (De Vries et al., 1999; Edelmann et al., 1999; Petukhova et al., 2005; Chi et al., 2007; Pezza et al., 2007). Kneitz et al., 2000). HFM1 is essential for mammalian fertility as In stark contrast to the exclusive inter-sister (IS) recombination mutated HFM1 was found in human patients with azoospermia or interactions occurring in the somatic cell cycle, MR interactions are POI syndromes (Baudat et al., 2013; Wang et al., 2014; Zhang et al., biased towards homologous chromosomes, thereby promoting 2017) and removing HFM1 causes a drastic reduction of COs and pairing, synapsis, and formation of chiasmata between partially affects synapsis in mice (Guiraldelli et al., 2013). The homologous chromosomes. The precise mechanism of this deficiency of SHOC1, TEX11, and SPO16 causes reduced COs meiotic inter-homolog (IH) bias is unclear but is likely achieved with a relatively minor synapsis defect in mice, suggesting a both by inhibiting IS bias and promoting IH bias. The so-far best- conserved role in CO formation as in yeast (Adelman and understood mechanism was uncovered in yeast, involving Tel1/ Petrini, 2008; De Muyt et al., 2018; Guiraldelli et al., 2018; Zhang Mec1 (ATM/ATR), Hop1 (homolog of HORMAD1/2), effector et al., 2019b). Mouse RNF212 and HEI10, a ubiquitin-ligase, regulate kinase Mek1 (homolog of CHK2), and RAD54, an SWI/SNF- CO by modifying recombination factors (MutSγ) at CO-designated family ATPase (Subramanian and Hochwagen, 2014). sites in an antagonistic manner. Subsequently, stabilized In the contemporary meiotic recombination models that are recombination factors enable the recruitment of CO-specific largely built on yeast studies, single-strand invasions result in less factors (MLH1-MLH3, MutLγ) for CO maturation (Reynolds stable nascent joint molecules, presumably D-loops. The et al., 2013; Qiao et al., 2014; Hunter, 2015; Gray and Cohen, differentiation of D-loops leads to either NCOs via synthesis- 2016; Prasada Rao et al., 2017). dependent strand annealing (SDSA) or class I COs subject to During early recombination steps, STR/BTR is required for interference (details of CO interference will be discussed below) channeling early joint molecules into CO and non-CO pathways. via forming CO-specific intermediates single-end invasions (SEIs) Later, STR/BTR promotes the resolution of the final recombination and double Holliday junctions (dHJs) (Figure 1). D-loops are intermediates into NCOs by its dissolution activity via SDSA stabilized along the CO pathway to form SEIs, which are the (Hunter, 2015). Distinguishingly, in the CO pathway, the earliest detectable CO-specific joint molecules. Subsequently, SEIs resolution of joint molecules is mediated by the endonuclease become more stable dHJs joint molecules through a second-end activity of mismatch repair factors MLH1, MLH3, and EXO1 to capture coupled with DNA synthesis. Eventually, dHJs are resolved generate class I COs. MLH1 and MLH3 are invaluable markers of exclusively into class I COs. By contrast, unstable D-loops are not crossovers in the cytological analysis as they localize precisely to stabilized in the NCO pathway after the invading strand extends. future CO sites in many organisms (Kolas and Cohen, 2004). The nascent DNA is annealed to the other end of the broken DNA Additional factors are found to be required for class I CO molecule resulting in NCOs. Additionally, a minority of D-loops formation in mice, including HEI10 (discussed above), CNTD1, escape from these two pathways and generate NCOs and non- PRR19 and CDK2 (Holloway et al., 2014; Qiao et al., 2014; interfering class II COs (Baudat et al., 2013; Hunter, 2015; Ranjha Bondarieva et al., 2020). et al., 2018). For non-interfering class II COs, the resolution of joint The differentiation of the CO and NCO pathways is controlled molecules is mediated by structure-specific endonucleases, by a panel of factors through processing and stabilizing the Mus81, Yen1, and Slx1/4 in yeast and MUS81 in mice (Holloway recombination intermediates, including ZMM proteins and a et al., 2008; De Muyt et al., 2012; Zakharyevich et al., 2012). In mice, helicase complex, STR/BTR (yeast Sgs1–Top3–Rmi1, metazoan interfering COs are estimated to account for ~90% of COs BLM-TOPIIIα-RMI1-RMI2) (Hunter, 2015). ZMMs stabilize (Holloway et al., 2008; Serrentino and Borde, 2012), and recombinational joint molecules and promote the formation of consistently, the deletion of MLH1, MLH3, or EXO1 causes SC, ultimately required for class I CO formation. In budding significant loss of chiasmata and, consequently, mice sterility yeast, ZMMs are CO-specific. However, in mice and several (Baker et al., 1996; Edelmann et al., 1996; Lipkin et al., 2002; other species, ZMMs’ stabilization of recombinational Wei et al., 2003). interactions may be a prerequisite for CO designation, and Finally, another layer of control tightly regulates the outcome D-loops bound by ZMMs could also form NCOs products (De of DSB repair. CO numbers per meiosis show a low variation Vries et al., 1999; Edelmann et al., 1999; Kneitz et al., 2000; Higgins despite a much more considerable variation in the numbers of et al., 2008; Yokoo et al., 2012; De Muyt et al., 2014; Zhang et al. recombinational interactions. This phenomenon is called CO Liang, 2014). homeostasis, which is underpinned by the lower and upper limits ZMM is a group of functionally diverse proteins, and several for the CO numbers regulated by CO assurance and interference mammalian ZMM proteins have been identified to have a role in the (Martini et al., 2006; Rosu et al., 2011; Cole et al., 2012; Yokoo CO/NCO decision: MSH4, MSH5, TEX11, RNF212, HEI10, HFM1, et al., 2012; Hunter, 2015). CO assurance guarantees that each SHOC1, and SPO16. All of these proteins partially colocalize with homolog pair obtains at least one CO to segregate properly at recombination foci (defined by RAD51 and DMC1) on synapsed axes meiosis I. Meanwhile, interference is defined by an inhibitory (De Vries et al., 1999; Edelmann et al., 1999; Kneitz et al., 2000; zone around CO-designated sites where other DSBs are Adelman and Petrini, 2008; Guiraldelli et al., 2013; Guiraldelli et al., prevented from becoming COs. Interference results in COs 2018; Qiao et al., 2014; Prasada Rao et al., 2017; Zhang et al., 2019b). being widely and evenly spaced along the genome (Hillers, MSH4 and MSH5 are homologs of the bacterial MutS family of 2004; Berchowitz and Copenhaver, 2010; Zhang and Liang, mismatch repair proteins with no known function in mismatch 2014). Frontiers in Cell and Developmental Biology 08 frontiersin.org Huang and Roig 10.3389/fcell.2023.1127440 The molecular mechanisms responsible for CO assurance and the errors. If errors persist, this mechanism can eventually activate interference have been long elusive. Studies in various species have apoptosis to cull meiocytes in various organisms (Roeder, 2000; described different mechanisms regulating CO interference (Zhang Bhalla and Dernburg, 2005; Di Giacomo et al., 2005; Lu et al., 2010). and Liang, 2014; Zhang and Wang, 2014; Fowler et al., 2018; Capilla- In mammals, observations in mutant mice deficient in meiotic Pérez et al., 2021; France et al., 2021; Morgan et al., 2021). A study of recombination suggest that two genetically distinct surveillance fission yeast S. pombe suggests a clustering model, emphasizing DSB mechanisms contribute to the activation of the arrest in both interference as the basis for CO interference (Fowler et al., 2018). In males and females: the recombination (DNA damage) checkpoint this model, in each cluster containing several DSB hotspots, only one monitoring the DSB repair process and the synapsis checkpoint single DSB is formed. Given that DSBs are the precursors to COs, monitoring SC formation (Roeder, 2000; MacQueen and consequently, at most, a single CO is made in the chromosomal Hochwagen, 2011; Subramanian and Hochwagen, 2014; Joshi interval corresponding to the DSB hotspot-clustered interval et al., 2015). (Fowler et al., 2018). Studies in budding yeast described a stress- In males defective in DSB repair, like Trip13mod/mod and Dmc1−/− and-stress relief mechanism for CO interference (the ‘beam-film’ mice, most spermatocytes arrest before incorporating the testis- model), which is SC independent and requires topoisomerase II specific histone 1t (H1t) at pachynema (Barchi et al., 2005; Marcet- (Zhang and Liang, 2014; Zhang and Wang, 2014). Distinctly, recent Ortega et al., 2017; Testa et al., 2018). In contrast, Spo11−/− work in Arabidopsis demonstrated that the SC is essential for CO spermatocytes, which do not have programmed DSBs, interference (Capilla-Pérez et al., 2021; France et al., 2021). Finally, a incorporate H1t and progress further, reaching mid/late new model (the diffusion-mediated coarsening model) is proposed pachytene. These cells arrest before completing the meiotic to explain CO interference (Morgan et al., 2021). These models may prophase and ultimately apoptose (Barchi et al., 2005; Pacheco apply to some but likely not all species since the mechanism and et al., 2015). Therefore, irrespective of the common apoptosis control of meiotic recombination varies among species. consequence, spermatocytes respond differently to these two How the outcome of DSB repair is regulated in mice is poorly meiotic defects. Furthermore, the removal of DSBs confers a understood, and ATM may have a role in forming the obligate CO in Spo11-like phenotype to those DSB repair-deficient mutants the small pseudoautosomal region of homology between sex (Dmc1−/− and Trip13mod/mod) (Barchi et al., 2005; Li and chromosomes and controlling the numbers and distributions of Schimenti, 2007), indicating that separate checkpoints act COs on autosomes (Barchi et al., 2008). However, this molecular sequentially to mediate the apoptosis of these defective mechanism elucidated in S. pombe is likely conserved in diverse spermatocytes. organisms, including flies and mice, based on the features of meiotic Likewise, in females, the elimination of oocytes defective for DSB recombination and pericentric regions in these species (Prieto et al., repair (Trip13mod/mod) or both DSB repair and synapsis (Dmc1−/−, 2001; Manheim and McKim, 2003; Fukuda et al., 2012; Msh5−/−) occurs earlier (around birth) than those defective for Bhattacharyya et al., 2019; Hartmann et al., 2019; Smith and synapsis alone (Spo11−/−, up to 2 months postpartum) (Di Nambiar, 2020). Giacomo et al., 2005; Li and Schimenti, 2007). Also, mutations disrupting DSB formation (Spo11 and Mei1) are epistatic to those affecting DSB repair (Dmc1, Atm, Trip13, and Mcmdc2) (Di 2.3 Meiotic prophase surveillance Giacomo et al., 2005; Reinholdt and Schimenti, 2005; Li and mechanisms Schimenti, 2007; Finsterbusch et al., 2016; Martínez-Marchal et al., 2020). These lines of evidence further support the existence DSB repair and synapsis are carefully monitored during the of two distinct checkpoint mechanisms in mammals, sensing DNA meiotic prophase to choreograph nuclear dynamics and cell damage or synapsis errors and resulting in meiotic prophase arrest. division programs. An intricate meiotic checkpoint network has However, there are also arguments against a specific “synapsis emerged to create dependencies between independent processes checkpoint”, at least in females, favoring that a canonical DNA when homologous chromosomes pair, synapse, and recombine. damage checkpoint primarily accounts for the oocyte loss in The machinery of this meiotic checkpoint involves many canonical response to both recombination and synapsis defects (discussed DNA damage response (DDR) signaling proteins, among which the below) (Rinaldi et al., 2017; Rinaldi et al., 2020). two evolutionarily conserved sensor kinases, ATM and ATR, play a central role (MacQueen and Hochwagen, 2011). They detect and 2.3.1 The recombination checkpoint respond to DSBs with the help of checkpoint cofactors in many The recombination checkpoint is likely activated when organisms. Once activated, ATM and ATR phosphorylate a large recombination intermediates persist at pachynema in mammals set of substrates, preferentially containing serine/threonine-glutamine (Di Giacomo et al., 2005; Burgoyne et al., 2009; MacQueen and (S/TQ) cluster domains (Traven and Heierhorst, 2005). Many of these Hochwagen, 2011). So far, the study of the recombination target proteins act directly to implement the checkpoint response, checkpoint in mammals has been challenged because most while others work as transmitters to relay the checkpoint signals to mutations that compromise recombination also affect synapsis. downstream effectors, such as CHK1 and CHK2 kinases However, a gene-trap-disrupted allele of Trip13, Trip13mod/mod (Subramanian and Hochwagen, 2014). This section will discuss (also known as Trip13RRB047RRB047, X. Li and Schimenti, 2007; Roig how the surveillance mechanisms of the meiotic prophase et al., 2010), which cannot repair DSBs but completes synapsis, has checkpoint monitor these meiotic events, particularly in mammals. proven to help study the recombination-dependent arrest and In response to DSB repair or synapsis defects, the cells trigger a meiocyte elimination. Analyses of mice doubly or triply deficient cell cycle arrest at the pachytene stage to provide sufficient time to fix for TRIP13 and other DDR genes uncovered several signaling Frontiers in Cell and Developmental Biology 09 frontiersin.org Huang and Roig 10.3389/fcell.2023.1127440 The MRN complex is responsible for DSBs sensing and activating ATM in somatic cells (Stracker and Petrini, 2011). It is also required for meiotic recombination in many organisms, including mammals (Keeney and Neale, 2006; Cherry et al., 2007). CHK2 is an effector kinase of the ATM signaling pathway activated in response to ionizing radiation (Matsuoka et al., 1998). Interestingly, disruption of the MRN complex or the CHK2 kinase in Trip13mod/mod mutants confers a meiotic progression phenotype similar to Trip13mod/mod Spo11+/−Atm−/− mutants (Pacheco et al., 2015). Thus, the MRN-ATM-CHK2 signaling cascade is likely to respond to persistent unrepaired DSBs, mediating the recombination-dependent pachytene arrest in male mice (Pacheco et al., 2015). Similarly, p53 and TAp63, two canonical CHK2’s downstream targets (Lu et al., 2010; Bolcun-Filas et al., 2014), have been inferred to act in the recombination-dependent arrest mechanism. This is based on the observations that Trip13mod/mod p53−/− and Trip13mod/mod TAp63−/− spermatocytes can progress to an H1t- positive stage (Marcet-Ortega et al., 2017). In Trip13mod/mod mutants lacking ATM or with defective MRN complex, spermatocytes cannot correctly repair abundant DSBs caused by the disability of ATM’s negative feedback in DSBs formation (Lange et al., 2011; Pacheco et al., 2015). Thus these spermatocytes fail to FIGURE 2 complete synapsis, which impedes the sex body formation (Barchi Recombination checkpoint pathway. Model showing the et al., 2008; Burgoyne et al., 2009; Roig et al., 2010; Pacheco et al., proposed signaling pathway in response to unrepaired SPO11- 2015). On the contrary, in Trip13mod/mod Chk2−/−, Trip13mod/mod p53−/−, and dependent DSBs in male (left) and female (right) mice. Asterisks represent predicted checkpoint factors. In males, DSBs are Trip13mod/mod TAp63−/− spermatocytes, although the sex body is formed, sensed by the MRN complex, leading to the activation of ATM, which in sex chromosomes are not correctly silenced, which explains why these turn activates effector CHK2. CHK2 acts on target proteins p53 and spermatocytes eventually undergo arrest and apoptosis at late pachynema TAp63, which implement the recombination-dependent arrest that blocks progression to mid/late pachynema. In females, (Pacheco et al., 2015; Marcet-Ortega et al., 2017). These lines of evidence RNF212 prevents the repair of residual DSBs in the late prophase. further support an alternative arrest mechanism mediating sex body Unrepaired DSBs likely activate ATR, which may activate CHK2 before defects in male mice (Barchi et al., 2005) (discussed below). birth and CHK1 after birth. CHK1 and CHK2 signal to p53 and TAp3. Pro-apoptotic BCL-2 pathway components PUMA, NOXA, BAX, and In females, an ATR-CHK1/CHK2-p53/TAp63-PUMA/NOXA- other unknown factors act downstream to trigger oocyte apoptosis. BAX signaling pathway is proposed to mediate the DNA damage checkpoint response in the oocytes (Bolcun-Filas et al., 2014; Rinaldi et al., 2017; ElInati et al., 2020; Martínez-Marchal et al., 2020; Rinaldi et al., 2020) (Figure 2). pathways involved in the recombination checkpoint-mediated arrest Deletion of CHK2 rescues developing oocytes in 3-week-postnatal and/or apoptosis in both males and females (Bolcun-Filas et al., Dmc1−/− mice, although the absence of primordial follicles eventually 2014; Pacheco et al., 2015; Marcet-Ortega et al., 2017; Rinaldi et al., results in a nearly complete oocyte depletion by 2 months postpartum. 2017; Rinaldi et al., 2020). This pattern of oocyte loss is highly similar to that in Spo11−/− or In males, the MRN complex, ATM, CHK2, and the p53 family Spo11−/−Dmc1−/− mice, suggesting that the loss of CHK2 allows the members, p53 and TAp63, are required to arrest spermatocytes with deficient oocytes to surpass the DSB repair but not the synapsis arrest. unrepaired DSBs at early pachynema before incorporating H1t into Moreover, the deletion of CHK2 can reach a more successful rescue in the chromatin (Pacheco et al., 2015; Marcet-Ortega et al., 2017; Trip13mod/mod mice, which complete synapsis. Trip13mod/mod Chk2−/− Marcet-Ortega et al., 2022) (Figure 2). mice have a significant pool of oocytes at 3 weeks postpartum, many In Trip13mod/mod mice, spermatocytes enter pachynema with follicles at 2 months of age, and sustained fertility for many months. homologous chromosomes completely synapsed but with persisting Abundant γH2AX staining was detected in all dictyate Trip13mod/mod recombination intermediates. Thus, most spermatocytes arrest and Chk2−/− oocytes indicating the persistence of unrepaired DSBs like in undergo apoptosis at epithelial stage IV before incorporating the mid- Trip13mod/mod. Thus, CHK2 is required for the DNA-damage pachytene histone marker H1t (Li and Schimenti, 2007; Roig et al., checkpoint-mediated oocyte elimination (Bolcun-Filas et al., 2014). 2010; Pacheco et al., 2015). In comparison, in Trip13mod/mod The lack of p53 and TAp63 enables nearly a complete rescue of Spo11+/−Atm−/− triple mutant mice, where the activity of ATM is Trip13mod/mod oocytes. Compared to wild-type mice, indistinguishable removed, a significant proportion of spermatocytes accumulate H1t numbers of primordial and growing follicles are found in the triple despite containing high levels of unrepaired DSBs. Thus, eliminating mutant Trip13mod/mod p53−/− TAp63−/− mice (Rinaldi et al., 2020). ATM activity allows spermatocytes to progress further, from an H1t- Therefore, like in males, p53 and TAp63 might also act negative to an H1t-positive stage, despite having significant amounts downstream of CHK2 in the DNA-damage checkpoint pathway in of unrepaired DSBs. These findings suggest that ATM may be females. However, CHK2 deficiency only rescues Trip13mod/mod required for the recombination-dependent arrest at early oocytes to around one-third of wild-type levels (Bolcun-Filas et al., pachynema (Barchi et al., 2005; Pacheco et al., 2015). 2014), implying other factors might signal these two effectors p53 and Frontiers in Cell and Developmental Biology 10 frontiersin.org Huang and Roig 10.3389/fcell.2023.1127440 TAp63 in parallel with CHK2. Indeed, CHK1 is likely to perform this function (Martínez-Marchal et al., 2020; Rinaldi et al., 2020). Studies have shown that when CHK2 is absent in ovaries, CHK1 is activated by persistent DSBs and is responsible for eliminating Chk2−/− oocytes (Martínez-Marchal et al., 2020; Rinaldi et al., 2020) (Figure 2). Interestingly, the pro-apoptotic BCL-2-dependent pathway acts downstream of CHK2/p53/TAp63 and eliminates recombination- defective oocytes (ElInati et al., 2020). The BCL-2-dependent pathway consists of the known targets of p53 and TAp63 PUMA, NOXA, and BAX (Su et al., 2013). PUMA and NOXA or BAX deletion rescue oocyte numbers in DSB-repair mutants (Dmc1−/− and Msh5−/−). However, like CHK2 deletion, this rescue does not reach wild-type levels, indicating that other components of this pathway also control the oocyte population (Bolcun-Filas et al., 2014; Rinaldi et al., 2017; ElInati et al., 2020) (Figure 2). Indeed, other p53 targets (e.g., BAK, PERP, or CDKN1A) have been proposed to play a role in this mechanism (ElInati et al., 2020). Non-etheless, the factors acting upstream of CHK2 in the recombination checkpoint pathway are not clearly understood in females. The loss of ATM triggers oocyte elimination by DNA damage checkpoint in mice, which can be rescued by the deficiency of CHK2 to a degree similar to the rescue by CHK2 in Dmc1−/− ovaries (Bolcun-Filas et al., 2014; Rinaldi et al., 2020). Thus, it has been proposed that ATR, the other canonical DDR kinase, activates CHK2 in the recombination checkpoint pathway in females. Furthermore, RNF212, a SUMO ligase required for crossover formation, is also suggested to promote the apoptosis of DSB repair- defective oocytes since Rnf212 deletion significantly restores the oocyte pool at 18 days postpartum in DSB-repair mutant females (Msh4−/−) (Qiao et al., 2018). RNF212 is proposed to impede DSB repair via inter-sister FIGURE 3 recombination (IS-HR) by stabilizing the association of HORMAD1 along Meiotic response to asynapsis in male. Upper panel, meiotic desynapsed chromosome axes during the late prophase. Thus, residual silencing of the unsynapsed chromatin (MSUC). Axially located DSBs, the repair of which via IS-HR are prevented by RNF212, trigger proteins signal asynapsis and recruit ATR with cofactors, such as BRCA1. If asynapsis persists, ATR translocates to chromatin loops, CHK2-mediated DNA damage checkpoint, resulting in oocyte phosphorylating H2AX (γH2AX). This signaling spreads all over the elimination (Qiao et al., 2018; ElInati et al., 2020). chromatin with the help of MDC1, leading to the recruitment of Notably, in both spermatocytes and oocytes, a certain level of silencing factors for the irreversible silencing of this region. Lower panel, in wild-type spermatocytes, the physiological MSUC occurs at unrepaired DSBs is required to activate the recombination-dependent XY chromosomes (MSCI), resulting in the silencing of sex arrest pathways during the meiotic prophase (Marcet-Ortega et al., chromosome-linked lethal genes (Zfy1 and Zfy2). However, in Spo11−/− 2017; Rinaldi et al., 2017). This is particularly important in spermatocytes, despite extensive asynapsis, localized MSUC are triggered by SPO11-independent DSBs on unsynapsed autosomes. As spermatocytes, where DSBs on the X chromosome arms lacking BRCA1 accumulates at these DSB sites, MSCI fails to form, and lethal homologous partners are repaired using the sister chromatids at genes are expressed. mid-late pachytene, later than on autosomes (Page et al., 2012; Baudat et al., 2013). Thus, the DSB threshold level for arrest activation must be high enough, or all wild-type spermatocytes would be arrested. Only spermatocytes reaching the threshold debated: whether a specific surveillance mechanism monitoring could activate both p53 and p63, which work independently but asynapsis exists and how it senses it is unclear. Even if the synapsis additively to trigger apoptosis response (Marcet-Ortega et al., 2017). checkpoint exists, it might not be like a formal checkpoint response In females, the primordial follicle pool is wholely abolished in wild- (Cloutier et al., 2015; Turner, 2015; Rinaldi et al., 2017). In any case, the type ovaries when the newborn ovaries are exposed to more than meiotic silencing of the unsynapsed chromatin (MSUC) plays a vital 0.3 Gy of irradiation. This dosage induces 10.3 RAD51 foci per oocyte surveillance role in this so-called “synapsis checkpoint” in both males (Rinaldi et al., 2017). Therefore, like in males, a threshold level of DSBs and females (Burgoyne et al., 2009; Cloutier et al., 2015; Turner, 2015). also triggers cell arrest in females. The MSUC is a chromatin remodeling process by which unsynapsed regions are transcriptionally inactivated during meiotic 2.3.2 The syapsis checkpoint prophase I (Turner, 2015) (Figure 3). It is achieved through the Defects in chromosome axis formation or SC assembly can activate crosstalk between the axially located sensors signaling asynapsis, such a cell response to asynapsis independently of DSB formation in many as the axial component proteins HORMAD1/2 proteins (Wojtasz organisms, leading to cell cycle arrest and even apoptosis (MacQueen et al., 2009; Fukuda et al., 2010), and the loop-located effectors and Hochwagen, 2011). In mammals, this synapsis checkpoint is mediating gene silencing such as the histone variant H2AX Frontiers in Cell and Developmental Biology 11 frontiersin.org Huang and Roig 10.3389/fcell.2023.1127440 (Fernandez-Capetillo et al., 2003). HORMAD1 and HORMAD2 load into germ cell arrest. The MSUC factors, HORMAD1 and onto chromosome axes at leptonema and are depleted from the axes HORMAD2 would be the putative synapsis checkpoint components by TRIP13 as the homologs synapse (Wojtasz et al., 2009; Fukuda in females (Turner, 2015). et al., 2010; Roig et al., 2010; Koubova et al., 2014). By the late zygotene However, it seems that the response to asynapsis in females ca stage, HORMAD1/2 acts together with SYCP3 to recruit the breast not be simply explained only by this checkpoint signaling model. cancer 1 (BRCA1) protein to the unsynapsed axes (Turner et al., 2004; Other mechanisms are also proposed to account for the loss of Kouznetsova et al., 2009; Royo et al., 2013). Then, in a HORMAD1/2- oocytes harboring asynapsis: the MUSC might render oocytes and BRCA1-dependent manner, ATR is recruited to unsynapsed axes deficient in multiple gene products required for oocyte survival (Turner et al., 2004; Wojtasz et al., 2012; Paigen and Petkov, 2018), and development (Cloutier et al., 2015; Cloutier et al., 2016). which further promotes the enrichment of BRCA1 and ATR- In mouse models carrying extra/supernumerary chromosomes, activating cofactors: TOPBP1, ATRIP (Perera et al., 2004; Refolio oocytes with asynapsed chromosomes are not eliminated as in XO et al., 2011; Royo et al., 2013) as well as regulate phosphorylation of females, despite the presence of HORMAD1 and other meiotic HORMAD1/2 (Fukuda et al., 2012). If asynapsis persists until silencing factors on the asynaptic supernumerary chromosomes pachytene, ATR translocates into the chromatin loops and (Cloutier et al., 2015). Silencing these asynaptic supernumerary phosphorylates H2AX (γH2AX) with the help of the γ-H2AX- chromosomes does not affect the normal gene expression from binding factor MDC1, resulting in the irreversible silencing of this the entire genome. In contrast, asynapsis of chromosomes in XO or region (Ichijima et al., 2011). other chromosomally unbalanced females would likely lead to the In males, spermatocyte loss mediated by the DSB-independent silencing of multiple housekeeping genes, oogenesis-essential genes, response to asynapsis involves the failure of Meiotic Sex or critical genes. Therefore, the fate of oocytes with asynapsis Chromosome Inactivation (MSCI) (Burgoyne et al., 2009) (Figure 3). probably depends on the gene content of the silenced asynapsed MSCI is a physiological MSUC process that responds to the unavoidable chromosomes (Cloutier et al., 2015; Turner, 2015). In Spo11−/− partial asynapsis of the sex chromosomes (Turner et al., 2006). MSCI is oocytes, chromosomes are extensively unsynapsed, and the reflected by the formation of the sex body, a specialized subnuclear MSUC takes place on only a part of them (Carofiglio et al., domain encompassing the asynapsed portions of the X and Y 2013). This MSUC might silence some essential genes (e.g., chromosomes in pachytene spermatocytes. The sex body is oogenesis-essential genes), leading to oocyte arrest and ultimately characterized by the lack of gene expression and sequestration of an triggering oocyte death. The rescue of oocyte loss by the deletion of array of proteins, which are primarily heterochromatin-related (e.g., silencing components HORMADS and H2AX in Spo11−/− mice and H2A, H3meK9, CBX1/3) and recombination-related (e.g., MRE11, other asynapsis models (Daniel et al., 2011; Wojtasz et al., 2012; γH2AX, and RAD51) (Handel, 2004). In mutant mice with extensive Cloutier et al., 2015) could be explained by the restoration of asynapsis (e.g., Spo11−/−, Dmc1−/−), MSCI cannot occur, and the sex body standard gene expression patterns, rather than the disruption of fails to form, likely due to the limited association of silencing factors with checkpoint signaling per se (Turner, 2015). the XY axes (Mahadevaiah et al., 2008; Kouznetsova et al., 2009). At the Recent findings show that the CHK2-dependent DNA damage zygotene/pachytene transition in wild-type spermatocytes, as DSBs get checkpoint also culls SPO11-deficient oocytes (Rinaldi et al., 2017; repaired, BRCA1 is released from the DSB sites and accumulates at the Rinaldi et al., 2020). These data argue against the existence of a HORMAD1-coated asynapsed XY axes, initiating MSCI response specific synapsis-checkpoint mechanism. Most Spo11−/− oocytes (Mahadevaiah et al., 2008; Burgoyne et al., 2009). However, in have some DSBs (Carofiglio et al., 2013; Malki et al., 2014). mutants with extensive asynapsis, BRCA1 is widely sequestered at Thus, authors speculate that it could be enough to reach the unrepaired SPO11-dependent DSB sites (e.g., Dnmt3l−/−), thus failing threshold to trigger the CHK2-dependent recombination to form MSCI (Mahadevaiah et al., 2008) or accumulates at SPO11- checkpoint (Rinaldi et al., 2017). So, a model in which two major independent DSB sites, randomly triggering localized MSUC response at mechanisms are responsible for the elimination of oocytes with autosomal axes (Carofiglio et al., 2013). As a result, lethal sex synapsis defect is proposed: the meiotic silencing mechanism, as chromosome-linked genes (e.g., Zfy1 and Zfy2) are expressed, leading discussed above, which primarily works in oocytes with a small to spermatocyte progression arrest and apoptosis (Royo et al., 2010). number of asynapsed chromosomes that carry meiotic-essential Thus, physiological MSCI is required to allow the exit of the pachytene genes but the amount of unrepaired DSBs does not reach the stage. threshold (Cloutier et al., 2015). The recombination checkpoint On the other hand, females possess two X chromosomes; thus, could function in oocytes with multiple asynapsed chromosomes MSCI does not occur in the oocytes. So, the roles of the MSUC in (e.g., Spo11−/− oocytes) that accumulate a sufficient number of DSBs response to asynapsis are different from that in males (Cloutier et al., to trigger the checkpoint (Rinaldi et al., 2017; Rinaldi et al., 2020). 2015; Turner, 2015) (Figure 4). Interestingly, the CHK2 deficiency can only restore a limited In asynapsis models without associated recombination defects, such number of Spo11−/− oocytes (Rinaldi et al., 2017; Martínez-Marchal as Spo11−/− mice and mice harboring chromosome abnormalities, such et al., 2020). Also, HORMAD2 and CHK2 are not functioning in a as Turner syndrome (XO) with only one X chromosome, unsynapsed single linear checkpoint pathway (Rinaldi et al., 2017; Martínez- chromosomes undergo MSUC, and oocytes with these unsynapsed Marchal et al., 2020). Therefore, other mechanisms eliminating most chromosomes are eliminated (Daniel et al., 2011; Wojtasz et al., 2012; of the Spo11−/− oocytes cannot be excluded, for instance, through the Cloutier et al., 2015). Deletion of the MSUC factors HORMAD1 or MSUC mechanism and/or the CHK1-dependent DNA damage HORMAD2 in Spo11−/− mice (Daniel et al., 2011; Wojtasz et al., 2012) checkpoint (Rinaldi et al., 2017; Martínez-Marchal et al., 2020). or H2AX in XO mice (Cloutier et al., 2015) restores the oocyte numbers Moreover, the lack of both p53 and TAp63 can protect nearly all to wild-type levels. Thus, the MSUC is suggested to transduce asynapsis Spo11−/− oocytes from elimination. However, the deletion of the Frontiers in Cell and Developmental Biology 12 frontiersin.org Huang and Roig 10.3389/fcell.2023.1127440 FIGURE 4 Meiotic response to asynapsis in female. Several mechanisms are proposed to be responsible for eliminating Spo11−/− oocytes. MSUC might trigger an unknown checkpoint signaling pathway in these oocytes or silence essential genes for development, leading to oocyte apoptosis. In parallel, in response to SPO11-independent DSBs, CHK2-mediated DNA damage signaling, which partially overlaps the recombination checkpoint pathway, also contributes to the elimination of Spo11−/− oocytes. BCL-2 components (PUMA, NOXA, and BAX) does not rescue the are suggested in infertility and need to be uncovered (Zorrilla and oocyte loss in Spo11−/− females (ElInati et al., 2020). These data Yatsenko, 2013). suggest that at least two distinct and partially overlapping genetic Male infertility derives etiologically from quantitative signaling pathways likely respond to recombination and synapsis spermatogenic defects, ductal obstruction or dysfunction, errors in females. Noticeably, a more recent study showed that hypothalamic-pituitary axis dysfunction, and qualitative RAD51 might not be a reliable DSB marker in oocytes, and although spermatogenic defects (from most to least common) (Tournaye DNA damage signaling from asynaptic axes participates in et al., 2017). Genetic factors account for at least 15% of male removing Spo11−/− oocytes, it does not require high numbers of infertility and involve all these etiological categories (Krausz and SPO11-independent DSBs as suggested in the study from Carofiglio Riera-Escamilla, 2018). Diagnosing male infertility relies on semen et al (Carofiglio et al., 2013; Ravindranathan et al., 2022). (and hormone) analysis, which results in two major phenotypes: Collectively, compared to the recombination checkpoint, the oligozoospermia (reduced sperm count) and azoospermia (no genetic pathways responsible for the “synapsis checkpoint” control spermatozoa in the ejaculate) (Tüttelmann et al., 2018). remain much less understood in both males and females. Rather Qualitative spermatogenic defects or ductal obstruction usually than being a typical checkpoint, the surveillance mechanisms that manifest as azoospermia, and multiple genetic factors are respond to asynapsis in mammals might be more complex. At least validated as the causes, including numerical and structural in females, the DNA damage signaling pathway, the MSUC- chromosomal anomalies (e.g., Klinefelter’s syndrome, 46, XX mediated checkpoint signal-transducing, and the depletion of male syndrome), Y-chromosome micro-deletions (e.g., essential genes for oocyte development and survival might azoospermia factor (AZF) deletions), gene mutations (e.g., conspire to drive the elimination of oocytes with asynapsed TEX11 deletions), and cystic fibrosis transmembrane conductance chromosomes. regulator (CFTR) mutations (Krausz and Riera-Escamilla, 2018). AZF deletions are the most frequent genetic cause of azoospermia (Krausz et al., 2014). Most numerical and structural chromosomal 3 Genetic cause of infertility anomalies and TEX11 deletions are thought to cause spermatogenic defects due to errors during meiosis that activate the surveillance Successful reproduction requires the precise regulation of mechanisms (Sun et al., 2007; Yang et al., 2015; Yatsenko et al., complex processes essential for developing reproductive organs, 2015). Currently, some of these genetic infertility causes can be performing gametogenesis, acquiring neuroendocrine clinically diagnosed by widely applied analyses, such as karyotyping, competency, and the ability to carry a pregnancy (Yatsenko and AZF deletion screening, and CFTR mutation analysis (Tournaye Rajkovic, 2019). Infertility, a common, multifactorial pathological et al., 2017). condition defined as the inability to establish a clinical pregnancy Female infertility can result from a wide range of factors after at least 1 year of regular unprotected sexual intercourse, affects affecting ovarian development, oocyte maturation, fertilization approximately 50 million couples worldwide (Mascarenhas et al., competence, and the potential of a fertilized egg for implantation 2012). Among the infertility cases with identified causes, one-third is and development (Yatsenko and Rajkovic, 2019). Ovulation due to a female factor, another third is due to a male factor, and the disorders are the leading cause of female infertility, which often remaining third is due to combined female and male factors occur as a result of conditions classified into three categories: (Mallepaly et al., 2017). Furthermore, genetic defects contribute hypothalamic failure, dysfunction of hypothalamic-pituitary- to nearly 50% of these infertility cases. More unknown genetic causes ovarian axis-mostly polycystic ovary syndrome (PCOS), and Frontiers in Cell and Developmental Biology 13 frontiersin.org Huang and Roig 10.3389/fcell.2023.1127440 primary ovarian insufficiency (POI) (National Institute for Health 2022). Advanced filtering techniques are required for selecting the and Care Excellence, 2013). Genetic factors are suggested to play a bona fide causes of human infertility from the discovered genes or role in all these disorders. For example, mutations of the GNRHR gene variants, and mouse studies are the gold standard for defining gene encoding the gonadotropin-releasing hormone (GnRH) the genotype-phenotype connection in fertility, at least in males receptor and genes causing Kallmann syndrome have been (Houston et al., 2021). Moreover, functional studies in mouse identified in women affected by hypothalamic amenorrhea. models are usually prerequisites to attributing a disease-causing Alternations in multiple genes such as CYP17, CYP19, LHCGR, role to a newly discovered gene (Riera-Escamilla et al., 2019), thus DENND1A are linked to PCOS, suggesting its polygenicity offering a panel of strong candidate genes for screening human (reviewed in Beke, 2019). infertility factors. POI has become a significant cause of female infertility due to Here, we summarized genes that are functionally involved in premature exhaustion of the primordial follicular pool in most cases meiotic prophase I, and mutating any of them could trigger (Rossetti et al., 2017). The most common contributors to POI are the recombination/synapsis checkpoint, leading to spermatocyte X chromosome-linked defects, in which Turner syndrome (TS) is arrest in males and/or oocyte depletion in females the primary cause of syndromic POI. In contrast, premutation of the (Supplementary Table S1). FMR1 (fragile X mental retardation 1) gene is the most common Of these 77 genes, many of them have essential roles in gene mutation associated with non-syndromic POI. In most cases of chromosome pairing, synapsis, and meiotic recombination POI, the activation of the surveillance mechanisms leading to a (detailed roles are discussed above), including components of the reduced ovarian reserve are responsible for infertility. For instance, chromosome axis or the SC, recombination factors required for DSB the absence of one X chromosome in TS causes oocyte loss during formation and repair, or proteins participating in telomere- early meiotic prophase and ovarian development, leading to ovarian mediated chromosome movements. The rest are mainly dysgenesis and primary amenorrhea since infancy (Fechner et al., functionally related to silencing retrotransposons, chromatin 2006). In other cases, how particular mutations (e.g., modification, and transcriptional and translational regulation of FMR1 premutation) lead to POI is not clear yet. The essential proteins required for SC formation and DSB repair. FMR1 premutation may cause a deficiency of proteins required Intriguingly, more than half of these meiosis-deficient mutants for oocyte or follicle development and survival (Rossetti et al., 2017). display sexually dimorphic phenotypes. Less stringent checkpoint Even though nowadays POI cannot be reverted, the identification of controls in females could explain these phenotypic differences. the causative genetic alterations in POI patients is beneficial for her Consequently, oocytes could tolerate more meiotic prophase I female relatives, who can undertake precautionary measures (e.g., error, which would explain why oogenesis is more error-prone egg freezing, embryo cryopreservation, anticipated pregnancy than spermatogenesis (Hunt and Hassold, 2002). In male mice planning, etc.) in case of being positive in the genetic screening deficient for Brca2, Mei1, Hormad1, Smc1b, or Sycp3 genes, (Rossetti et al., 2017). This perspective is becoming increasingly spermatocytes are arrested at the pachytene stage due to the important due to the modern tendency to delay childbirth in defective meiotic prophase events, resulting in male sterility societies. (Supplementary Table S1). However, these mutant oocytes are Despite the revealed genetic factors contributing to female and only partially arrested at meiotic prophase I in females, and some male infertility, many genetic causes remain unexplained for the progress beyond prophase I despite carrying asynaptic homologs, majority of infertility cases, including idiopathic infertility cases, unrepaired DSBs, or other chromosomal abnormalities. Other which are identified in 25%–30% of infertility couples and likely mechanisms during oogenesis can eliminate these defective have a genetic etiology (Smith et al., 2003; Mallepaly et al., 2017). oocytes later, but some even complete meiosis and form Furthermore, with the increasing use of assisted reproductive unbalanced oocytes. As a result, some of these meiosis-deficient technology (ART), which removes the natural barrier to egg mutant females are even subfertile (Reinholdt and Schimenti, 2005; fertilization, concerns about its safety and possible adverse Daniel et al., 2011; Felipe-Medina et al., 2020). outcomes are rising (Davies et al., 2012). Diagnosing the genetic Another explanation could be that some of these genes have causes of infertility becomes more clinically significant for infertility sexually dimorphic roles. For example, Hells and Rad21l genes have treatment and the health of patients and their children. Thus, distinct roles in males and females. While the deficient males are identifying unknown genes involved in mammalian infertile due to meiotic prophase I arrest, the mutant females exhibit gametogenesis, which could contribute to human infertility, is lethality (Hells), or subfertility (Rad21l), due to other defects rather demanding and essential for clinical infertility diagnosis in the than failed synapsis or incomplete meiotic recombination. On the near future. other hand, Asz1, Dnmt3l, Mybl1, Mov10l1, Piwil2, Piwil4, Pld6, and Tdrd9 are specifically required for the silencing of retrotransposons in males, while Dmrt7 has significant roles in meiotic silencing of the 3.1 Mutations of meiotic prophase genes in XY chromosomes which only exist in spermatocytes. Thus, the mice disruption of these genes causes male infertility due to a complete arrest in spermatocytes, but female fertility is grossly unaffected In recent years, advances in genomic approaches, particularly (Supplementary Table S1). next-generation sequencing (NGS) technologies, allowed unbiased Furthermore, some recombination factors, such as BRCA1, genomic studies of human infertility and uncovered many BRME1, MEILB2, and TEX15, recruit recombinases RAD51/ infertility-associated genes or gene variants in males and females DMC1 to DSB sites in spermatocytes. The mutations of these (Yatsenko and Rajkovic, 2019; Precone et al., 2021; Heddar et al., genes result in male infertility but only have mild or no effects Frontiers in Cell and Developmental Biology 14 frontiersin.org Huang and Roig 10.3389/fcell.2023.1127440 on female fertility (Supplementary Table S1). While if they have differences still exist between humans and mice (Azhar et al., 2021). A similar roles in females is unclear or cannot be excluded, the milder recent study has shown that the metaphase checkpoint is more phenotypes in female mutant mice might be a consequence of frequently activated than the pachytene checkpoint in human males combined effects from the weak checkpoint control and less- with severe spermatogenic impairment (Enguita-Marruedo et al., 2019), required roles during meiotic recombination in oocytes. which is in contrast to observations in the mouse, where knockout of the In humans, meiotic defects typically result in non-obstructive meiotic prophase genes (as we summarized above) most frequently azoospermia (NOA), whereas in females, they are usually associated results in pachytene checkpoint arrest. The underlying reasons are not with POI (Krausz et al., 2020). We searched these 77 meiotic clear. It could be that the observed arrest in this study is caused mainly prophase genes, the mutation of which could trigger meiotic by mutations in proteins required for the metaphase-anaphase prophase arrest in mice, in ClinVar and Pubmed, and found transition or functioning in cell cycle regulation rather than involved monogenetic mutations of 28 genes (145 variants) have been in meiotic prophase major events (Enguita-Marruedo et al., 2019). reported to be associated with human infertility conditions such Alternatively, mutation of meiotic prophase genes may trigger a later as spermatogenetic failure, NOA, POI, spermatogenesis maturation metaphase arrest in humans rather than prophase arrest in mice. arrest, pregnancy loss, etc. (Supplementary Table S2). Differences in the pachytene surveillance mechanisms between Based on the interpretations for clinical significance in ClinVar, humans and mice could cause this. Most studies (58 out of 55 of these variants are considered as “likely pathogenic” or “uncertain 78 publications in Supplementary Table S1) reporting mutations of significance” (Supplementary Table S2). This is mainly due to the lack meiotic prophase genes in infertile males lack detailed analysis of of evidence or inconsistent interpretations. Of the 145 variants, meiotic or testicular phenotypes. Thus, to clarify this possibility, it 67 variants from 21 genes are classified as ‘pathogenic’, 52 variants will be worthwhile to assess the exact spermatocyte arrest phase in from 16 genes have only 1 or 2 publications reporting independent infertile patients carrying meiotic prophase gene mutations in the probands, and single submitters provide the remainder without future. publications. Moreover, only five variants from five genes (Six6os1, Meilb2, Msh5, Stag3, and Syce1) have supporting biological evidence from knockout mouse models in which human phenotypes are Author contributions recapitulated (Supplementary Table S2). Thus, in the future, more independent validation studies and functional evidence are required, YH and IR conceived and wrote the manuscript. including introducing gene variants using CRISPR/Cas9 genome editing technology in mice to validate the infertility-causing roles of human gene variants (Houston et al., 2021), not only for distinguishing Funding between variants that cause disease from variants that are rare but benign (Araujo et al., 2020), but also for providing robustness to the YH is a recipient of a fellowship from the China Scholarship clinical validity of these possible disease-causing genes linked to human Council (201607040048). This work was supported by Spanish infertility (Oud et al., 2019). Ministerio de Economía y Competividad grants to IR(PID 2019- Additionally, multiple levels of evidence should also be 107082RB-I00) and a grant from La Funació Marató de TV3 (677/ considered to confidently link variation in individual genes to U/2021). human infertility (Oud et al., 2019). Indeed, an unstructured assessment has reported three genes, including Tex11, that fulfill this requirement for a link to male infertility (Tüttelmann et al., Conflict of interest 2018). Recently, in another study of an extensive literature review and standardized clinical validity assessment of a large number of The authors declare that the research was conducted in the genes, some of these meiotic prophase genes were shown to be absence of any commercial or financial relationships that could be associated with male infertility with ‘strong’ evidence (Tex11 and construed as a potential conflict of interest. Tex15), with ‘moderate’ evidence (Sycp3), or with ‘limited’ evidence (Dmc1, Mei1, Meiob, Spo11, Syce1, and Tdrd9) (Oud et al., 2019). Importantly, the associated conditions of all these 28 genes in Publisher’s note humans are well matched with the phenotypes of their mutant mice (Supplementary Table S2). For example, the mutation of SYCP3 causes All claims expressed in this article are solely those of the authors and male infertility with complete meiotic prophase arrest. Still, it exhibits do not necessarily represent those of their affiliated organizations, or subfertility in female mice with a sharp reduction in litter size due to the those of the publisher, the editors and the reviewers. Any product that presence of aneuploid oocytes. Correspondingly, its linked conditions in may be evaluated in this article, or claim that may be made by its humans are infertility/spermatogenetic failure in men and pregnancy manufacturer, is not guaranteed or endorsed by the publisher. loss in women. This further support the values of mouse models for attributing a disease-causing role to a new gene. Thus, the remaining meiotic prophase genes with no monogenic mutation identified in this Supplementary material list are worthy of screening in human patients. 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