Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis
Penas Pérez, Clara (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Maloof, M. E. (University of Miami Miller School of Medicine. Center for Therapeutic Innovation. Department of Psychiatry and Behavioral Sciences)
Stathias, V. (University of Miami Miller School of Medicine. Center for Therapeutic Innovation. Department of Psychiatry and Behavioral Sciences)
Long, J. (University of Miami Miller School of Medicine. Department of Surgery)
Tan, S. K. (University of Miami Miller School of Medicine. Department of Psychiatry and Behavioral Sciences)
Mier, J. (University of Miami Miller School of Medicine. Department of Neurosurgery. Miami Project to Cure Paralysis)
Fang, Y. (The Rockefeller University. Laboratory of Development Neurobiology)
Valdes, C. (Florida International University. Computing and Information Sciences)
Rodriguez-Blanco, J. (University of Miami Miller School of Medicine. Department of Surgery)
Chiang, C. M. (University of Texas Southwestern Medical Center. Simmons Comprehensive Cancer Center. Department of Biochemistry and Department of Pharmacology)
Robbins, D. J. (University of Miami Miller School of Medicine. Department of Surgery)
Liebl, D. J. (University of Miami Miller School of Medicine. Department of Surgery)
Lee, J. K. (University of Miami Miller School of Medicine. Department of Neurosurgery. Miami Project to Cure Paralysis)
Hatten, M. E. (The Rockefeller University. Laboratory of Development Neurobiology)
Clarke, J. (University of Nebraska. Department of Statistics)
Ayad, N. G. (University of Miami Miller School of Medicine. Department of Psychiatry and Behavioral Sciences. Center for Therapeutic Innovation. Sylvester Comprehensive Cancer Center. Miami Project to Cure Paralysis)

Date:	2019
Abstract:	Cerebellar neuronal progenitors undergo a series of divisions before irreversibly exiting the cell cycle and differentiating into neurons. Dysfunction of this process underlies many neurological diseases including ataxia and the most common pediatric brain tumor, medulloblastoma. To better define the pathways controlling the most abundant neuronal cells in the mammalian cerebellum, cerebellar granule cell progenitors (GCPs), we performed RNA-sequencing of GCPs exiting the cell cycle. Time-series modeling of GCP cell cycle exit identified downregulation of activity of the epigenetic reader protein Brd4. Brd4 binding to the Gli1 locus is controlled by Casein Kinase 1δ (CK1 δ)-dependent phosphorylation during GCP proliferation, and decreases during GCP cell cycle exit. Importantly, conditional deletion of Brd4 in vivo in the developing cerebellum induces cerebellar morphological deficits and ataxia. These studies define an essential role for Brd4 in cerebellar granule cell neurogenesis and are critical for designing clinical trials utilizing Brd4 inhibitors in neurological indications.
Note:	Altres ajuts: UM/CA103867
Note:	Altres ajuts: WF/I-1805
Note:	Altres ajuts: NIH/NS067289
Note:	Altres ajuts: NIH/R56102590
Note:	Altres ajuts: CPRIT/RP180349
Note:	Altres ajuts: CPRIT/RP190077
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Animals ; Animals, Newborn ; Casein Kinase Idelta ; Cell Cycle ; Cell Differentiation ; Cell Proliferation ; Cerebellar Ataxia ; Cerebellar Cortex ; Disease Models, Animal ; Down-Regulation ; Humans ; Mice ; Mice, Knockout ; Neural Stem Cells ; Neurogenesis ; Neurons ; Nuclear Proteins ; Phosphorylation ; Primary Cell Culture ; Transcription Factors ; Zinc Finger Protein GLI1
Published in:	Nature communications, Vol. 10 Núm. 1 (january 2019) , p. 3028, ISSN 2041-1723

DOI: 10.1038/s41467-019-10799-5
PMID: 31292434

11 p, 4.2 MB

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