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.
Highlights
Genes encoding cell-surface proteins control nervous system development and are implicated in neurological disorders
We focused on cell surface receptors of the epidermal growth factor (EGF), Immunoglobulin (Ig), and adhesion Gprotein coupled receptor superfamilies, as these genes have known roles in cell-cell recognition
Applying these tools to the developing nervous system, we uncovered a vast diversity of isoforms encoding cell surface proteins, most of which were unannotated elsewhere
Summary
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. Dysregulation of isoform expression is implicated in neurological disorders[9,10,11] For these reasons, there is increasing awareness that genetic studies of CNS development, function, and disease will need to take isoform diversity into account. Each of these genes produces hundreds of protein isoforms with distinct binding specificity, diversifying the molecular recognition events that mediate assembly of the nervous system[17,18,19] From these examples it seems clear that, to understand the molecular basis for neural circuit wiring, it will be necessary to define the precise repertoire of cell-surface protein isoforms expressed in the developing CNS. Comprehensive isoform identification has great potential to reveal how these genetic variants cause disease pathology
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