Comprehensive identification of mRNA isoforms reveals the diversity of neural cell-surface molecules with roles in retinal development and disease

Thomas A. Ray, Kelly Cochran, Chris Kozlowski, Jingjing Wang, Graham Alexander, Martha A. Cady, William J. Spencer, Philip A. Ruzycki, Brian S. Clark, Annelies Laeremans, Ming Xiao He, Xiaoming Wang, Emily Park, Ying Hao, Alessandro Iannaccone, Gary Hu, Olivier Fedrigo, Nikolai P. Skiba, Vadim Y. Arshavsky, Jeremy N. Kay

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Genes encoding cell-surface proteins control nervous system development and are implicated in neurological disorders. These genes produce alternative mRNA isoforms which remain poorly characterized, impeding understanding of how disease-associated mutations cause pathology. Here we introduce a strategy to define complete portfolios of full-length isoforms encoded by individual genes. Applying this approach to neural cell-surface molecules, we identify thousands of unannotated isoforms expressed in retina and brain. By mass spectrometry we confirm expression of newly-discovered proteins on the cell surface in vivo. Remarkably, we discover that the major isoform of a retinal degeneration gene, CRB1, was previously overlooked. This CRB1 isoform is the only one expressed by photoreceptors, the affected cells in CRB1 disease. Using mouse mutants, we identify a function for this isoform at photoreceptor-glial junctions and demonstrate that loss of this isoform accelerates photoreceptor death. Therefore, our isoform identification strategy enables discovery of new gene functions relevant to disease.

Original languageEnglish
Article number3328
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

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