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

• Type of Material: Article
• Authors: Anoushka Joglekar, Weill Cornell Medicine; Andrey Prjibelski, St Petersburg State University; Ahmed Mahfouz, Leiden University; Paul Collier, Weill Cornell Medicine; Susan Lin, Weill Cornell Medical College; Anna Katharina Schlusche, Weill Cornell Medicine; Jordan Marrocco, Rockefeller University; Stephen R. Williams, 10x Genom; Bettina Haase, Rockefeller University; Ashley Hayes, 10x Genom; Jennifer G. Chew, 10x Genom; Neil I. Weisenfeld, 10x Genom; Man Ying Wong, Weill Cornell Medicine; Alexander N. Stein, Columbia University; Simon A. Hardwick, Garvan Institute of Medical Research; Toby Hunt, European Bioinformatics Institute; Qi Wang, Heidelberg University Hospital; Christoph Dieterich, Heidelberg University Hospital; Zachary Bent, 10x Genom; Olivier Fedrigo, Rockefeller University; Steven Sloan, Emory University; Davide Risso, University of Padua; Erich D. Jarvis, Rockefeller University; Paul Flicek, European Bioinformatics Institute; Wenjie Luo, Weill Cornell Medicine; Geoffrey S. Pitt, Weill Cornell Medical College; Adam Frankish, European Bioinformatics Institute; August B. Smit, Vrije Universiteit Amsterdam; M. Elizabeth Ross, Weill Cornell Medicine; Hagen U. Tilgner, Weill Cornell Medicine
• Language: English
• Date: 2021-01-19
• Publisher: Nature Portfolio
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-020-20343-5
• Title of Journal or Parent Work: Nature Communications
• Volume: 12
• Issue: 1
• Start Page: 463
• End Page: 463
• Grant/Funding Information: This work was supported by the Brain Initiative (grant 1RF1MH121267-01 to H.U.T), NIGMS (grant 1R01GM135247-01 to H.U.T), NINDS (grant 1R01NS105477 to M.E.R), NIDA (T32DA03980 to S.L.), and NIMH (grant R01MH118934 to G.P.), Australian NHMRC Early Career Fellowship (APP1156531 to S.A.H), RFBR (grant 19-04-01074 to A.P.),; D.R. was supported by Programma per Giovani Ricercatori Rita Levi Montalcini granted by the Italian Ministry of Education, University, and Research, by the Chan Zuckerberg Initiative DAF, an advised fund of Silicon Valley Community Foundation (CZF2019-002443), and by the NCI (2U24CA180996),; S.A.S was supported by the Brain and Behavior Foundation NARSAD YIA and Sontag Foundation, P.F. was supported by NHGRI (grant 2U41HG007234), Wellcome (WT108749/Z/15/Z), and the European Molecular Biology Laboratory. E.D.J was supported by HHMI.
• Keywords: Science & Technology - Other Topics; Multidisciplinary Sciences; Science & Technology
• Research Categories: Biology, Bioinformatics; Biology, Genetics; Biology, Molecular; Biology, Neuroscience

Abstract

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.