A spatially resolved brain region- and cell type-specific isoform atlas of the postnatal mouse brain

• Published in: Nature communications Vol. 12; no. 1; p. 463
• Main Authors: Joglekar, Anoushka, Prjibelski, Andrey, Mahfouz, Ahmed, Collier, Paul, Lin, Susan, Schlusche, Anna Katharina, Marrocco, Jordan, Williams, Stephen R., Haase, Bettina, Hayes, Ashley, Chew, Jennifer G., Weisenfeld, Neil I., Wong, Man Ying, Stein, Alexander N., Hardwick, Simon A., Hunt, Toby, Wang, Qi, Dieterich, Christoph, Bent, Zachary, Fedrigo, Olivier, Sloan, Steven A., Risso, Davide, Jarvis, Erich D., Flicek, Paul, Luo, Wenjie, Pitt, Geoffrey S., Frankish, Adam, Smit, August B., Ross, M. Elizabeth, Tilgner, Hagen U.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 13/62; 38/39; 38/91; 631/114/116; 631/208/1792; 631/337/2019; 631/378/2571; Alternative splicing; Alternative Splicing - physiology; Animals; Animals, Newborn; Brain; Brain mapping; Choroid plexus; Computational Biology; Epithelium; Female; Gene Expression Regulation, Developmental - physiology; Hippocampus - cytology; Hippocampus - growth & development; Hippocampus - metabolism; Humanities and Social Sciences; Isoforms; Mice; Models, Animal; multidisciplinary; Prefrontal cortex; Prefrontal Cortex - cytology; Prefrontal Cortex - growth & development; Prefrontal Cortex - metabolism; Protein Isoforms - analysis; Protein Isoforms - genetics; Protein Isoforms - metabolism; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Single-Cell Analysis - methods; Spatial Analysis; Spatial discrimination; Spatial resolution; Splicing; Transcription; Transcriptomics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20343-5

Splicing varies across brain regions, but the single-cell resolution of regional variation is unclear. We present a single-cell investigation of differential isoform expression (DIE) between brain regions using single-cell long-read sequencing in mouse hippocampus and prefrontal cortex in 45 cell types at postnatal day 7 ( www.isoformAtlas.com ). Isoform tests for DIE show better performance than exon tests. We detect hundreds of DIE events traceable to cell types, often corresponding to functionally distinct protein isoforms. Mostly, one cell type is responsible for brain-region specific DIE. However, for fewer genes, multiple cell types influence DIE. Thus, regional identity can, although rarely, override cell-type specificity. Cell types indigenous to one anatomic structure display distinctive DIE, e.g. the choroid plexus epithelium manifests distinct transcription-start-site usage. Spatial transcriptomics and long-read sequencing yield a spatially resolved splicing map. Our methods quantify isoform expression with cell-type and spatial resolution and it contributes to further our understanding of how the brain integrates molecular and cellular complexity. Alternative RNA splicing varies across the brain. Its mapping at single cell resolution is unclear. Here, the authors provide a spatial and single-cell splicing atlas reporting brain region- and cell type-specific expression of different isoforms in the postnatal mouse brain.