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 and Jeremy N. Kay ()
Additional contact information
Thomas A. Ray: Duke University School of Medicine
Kelly Cochran: Duke University School of Medicine
Chris Kozlowski: Duke University School of Medicine
Jingjing Wang: Duke University School of Medicine
Graham Alexander: Duke University
Philip A. Ruzycki: John F. Hardesty, M.D. Department of Ophthalmology and Visual Sciences, Washington University
Brian S. Clark: John F. Hardesty, M.D. Department of Ophthalmology and Visual Sciences, Washington University
Annelies Laeremans: Advanced Cell Diagnostics
Ming-Xiao He: Advanced Cell Diagnostics
Xiaoming Wang: Advanced Cell Diagnostics
Emily Park: Advanced Cell Diagnostics
Ying Hao: Duke University School of Medicine
Alessandro Iannaccone: Duke University School of Medicine
Gary Hu: Duke University School of Medicine
Olivier Fedrigo: Duke University
Nikolai P. Skiba: Duke University School of Medicine
Vadim Y. Arshavsky: Duke University School of Medicine
Jeremy N. Kay: Duke University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-20

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17009-7

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