dcece3732d96fb4c993a7e73b756879f 306961.pdf ff6096766641c9ddf24f6548dbf9e4ccaa09f8fb 306961.pdf 64a3e4d94521bf3a5bebc1d0aea98ac9c480b80fb4062c106caef1971dc3132e 306961.pdf Title: Unique Splicing of Lrp5 in the Brain: A New Player in Neurodevelopment and Brain Maturation Subject: Low-density lipoprotein receptor-related protein 5 (LRP5) is a constitutively expressed receptor with observed roles in bone homeostasis, retinal development, and cardiac metabolism. However, the function of LRP5 in the brain remains unexplored. This study investigates LRP5’s role in the central nervous system by conducting an extensive analysis using RNA-seq tools and in silico assessments. Two protein-coding Lrp5 transcripts are expressed in mice: full-length Lrp5-201 and a truncated form encoded by Lrp5-202. Wt mice express Lrp5-201 in the liver and brain and do not express the truncated form. Lrp5-/- mice express Lrp5-202 in the liver and brain and do not express Lrp5-201 in the liver. Interestingly, Lrp5-/- mouse brains show full-length Lrp5-201 expression, suggesting that LRP5 has a role in preserving brain function during development. Functional gene enrichment analysis on RNA-seq unveils dysregulated expression of genes associated with neuronal differentiation and synapse formation in the brains of Lrp5-/- mice compared to Wt mice. Furthermore, Gene Set Enrichment Analysis highlights downregulated expression of genes involved in retinol and linoleic acid metabolism in Lrp5-/- mouse brains. Tissue-specific alternative splicing of Lrp5 in Lrp5-/- mice supports that the expression of LRP5 in the brain is needed for the correct synthesis of vitamins and fatty acids, and it is indispensable for correct brain development. Keywords: LRP5; brain; RNA-seq; liver; transcriptome; synapse; retinoic acid Author: Aureli Luquero, Noelia Pimentel, Gemma Vilahur, Lina Badimon and Maria Borrell-Pages Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Fri Jul 19 03:11:30 2024 CEST ModDate: Wed Jul 24 03:11:44 2024 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 18 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1872052 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- MWHIBA+VnURWPalladioL Type 1 Custom yes yes yes 10 0 NJGNXN+URWPalladioL-Bold Type 1 Custom yes yes yes 16 0 IZPPJD+URWPalladioL-Roma Type 1 Custom yes yes yes 22 0 MCJFGS+URWPalladioL-Ital Type 1 Custom yes yes yes 27 0 ECHHDN+URWPalladioL-BoldItal Type 1 Custom yes yes yes 32 0 BCMPRC+CMSY10 Type 1 Builtin yes yes 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BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 252 0 BCDIEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 256 0 OBGDHD+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 271 0 OBGDHE+PalatinoLinotype CID TrueType Identity-H yes yes yes 274 0 OBGDHF+PalatinoLinotype TrueType WinAnsi yes yes no 280 0 OBGDHH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 283 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-02-07 02:47:22 CET RepresentationInformation: 306961.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-02-06 19:40:59 CET Size: 1872052 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 495 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Non-Mendelian Pattern in Lrp5-/- Mouse Births Destination: subsection.2.1 Item: Title: LRP5 Is Expressed in Brains of Lrp5-/- Mice Destination: subsection.2.2 Item: Title: Lrp5 Transcriptome Is Different in Livers and Brains of Lrp5-/- Mice Destination: subsection.2.3 Item: Title: LRP5 Deficiency Leads to Alterations in the Transcriptome of Livers and Brains Destination: subsection.2.4 Item: Title: Lrp5 Quantity Is Different in Livers and Brains of Lrp5-/- Mice Destination: subsection.2.5 Item: Title: Functional Studies Show Modified Functions in Brains of Lrp5-/- Mice Destination: subsection.2.6 Item: Title: Functional Studies Show Impaired Functions in Livers of Lrp5-/- Mice Destination: subsection.2.7 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Animal Models and Experimental Design Destination: subsection.4.1 Item: Title: RNA Isolation and Real-Time PCR Destination: subsection.4.2 Item: Title: RNA-Seq Analysis Destination: subsection.4.3 Item: Title: In Silico Systems Biology Analysis Destination: subsection.4.4 Item: Title: Statistical Analysis Destination: subsection.4.5 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: appendix.A. Info: Title: Unique Splicing of Lrp5 in the Brain: A New Player in Neurodevelopment and Brain Maturation Author: Aureli Luquero, Noelia Pimentel, Gemma Vilahur, Lina Badimon and Maria Borrell-Pages Subject: Low-density lipoprotein receptor-related protein 5 (LRP5) is a constitutively expressed receptor with observed roles in bone homeostasis, retinal development, and cardiac metabolism. However, the function of LRP5 in the brain remains unexplored. This study investigates LRP5’s role in the central nervous system by conducting an extensive analysis using RNA-seq tools and in silico assessments. Two protein-coding Lrp5 transcripts are expressed in mice: full-length Lrp5-201 and a truncated form encoded by Lrp5-202. Wt mice express Lrp5-201 in the liver and brain and do not express the truncated form. Lrp5-/- mice express Lrp5-202 in the liver and brain and do not express Lrp5-201 in the liver. Interestingly, Lrp5-/- mouse brains show full-length Lrp5-201 expression, suggesting that LRP5 has a role in preserving brain function during development. Functional gene enrichment analysis on RNA-seq unveils dysregulated expression of genes associated with neuronal differentiation and synapse formation in the brains of Lrp5-/- mice compared to Wt mice. Furthermore, Gene Set Enrichment Analysis highlights downregulated expression of genes involved in retinol and linoleic acid metabolism in Lrp5-/- mouse brains. Tissue-specific alternative splicing of Lrp5 in Lrp5-/- mice supports that the expression of LRP5 in the brain is needed for the correct synthesis of vitamins and fatty acids, and it is indispensable for correct brain development. 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