Transcript isoforms of Reep6 have distinct functions in the retina.

TitleTranscript isoforms of Reep6 have distinct functions in the retina.
Publication TypeJournal Article
Year of Publication2021
AuthorsLiang, Q, Wu, N, Zaneveld, S, Liu, H, Fu, S, Wang, K, Bertrand, R, Wang, J, Li, Y, Chen, R
JournalHum Mol Genet
Date Published2021 Oct 13
KeywordsAlternative Splicing, Animals, Cerebral Cortex, Electroretinography, Eye Proteins, Fluorescent Antibody Technique, Gene Expression Regulation, Genotype, Humans, Immunohistochemistry, Membrane Proteins, Mice, Mice, Knockout, Phenotype, Photoreceptor Cells, Vertebrate, Protein Isoforms, Retina, RNA, Messenger

Much of the complexity of the eukaryotic cell transcriptome is due to the alternative splicing of mRNA. However, knowledge on how transcriptome complexity is translated into functional complexity remains limited. For example, although different isoforms of a gene may show distinct temporal and spatial expression patterns, it is largely unknown whether these isoforms encode proteins with distinct functions matching their expression pattern. In this report, we investigated the function and relationship of the two isoforms of Reep6, namely Reep6.1 and Reep6.2, in rod photoreceptor cells. These two isoforms result from the alternative splicing of exon 5 and show mutually exclusive expression patterns. Reep6.2 is the canonical isoform that is expressed in non-retinal tissues, whereas Reep6.1 is the only expressed isoform in the adult retina. The Reep6.1 isoform-specific knockout mouse, Reep6E5/E5, is generated by deleting exon 5 and a homozygous deletion phenotypically displayed a rod degeneration phenotype comparable to a Reep6 full knockout mouse, indicating that the Reep6.1 isoform is essential for the rod photoreceptor cell survival. Consistent with the results obtained from a loss-of-function experiment, overexpression of Reep6.2 failed to rescue the rod degeneration phenotype of Reep6 knockout mice whereas overexpression of Reep6.1 does lead to rescue. These results demonstrate that, consistent with the expression pattern of the isoform, Reep6.1 has rod-specific functions that cannot be substituted by its canonical isoform. Our findings suggested that a strict regulation of splicing is required for the maintenance of photoreceptor cells.

Alternate JournalHum Mol Genet
PubMed ID34104971
PubMed Central IDPMC8522633
Grant ListP30 CA125123 / CA / NCI NIH HHS / United States
S10 OD023469 / OD / NIH HHS / United States
P30 EY002520 / EY / NEI NIH HHS / United States
R01 EY022356 / EY / NEI NIH HHS / United States

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