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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Ray, TA; Cochran, K; Kozlowski, C; Wang, J; Alexander, G; Cady, MA; Spencer, WJ; Ruzycki, PA; Clark, BS; Laeremans, A; He, M-X; Wang, X; Park, E; Hao, Y; Iannaccone, A; Hu, G; Fedrigo, O; Skiba, NP; Arshavsky, VY; Kay, JN

Published Date

  • July 3, 2020

Published In

Volume / Issue

  • 11 / 1

Start / End Page

  • 3328 -

PubMed ID

  • 32620864

Pubmed Central ID

  • PMC7335077

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-020-17009-7


  • eng

Conference Location

  • England