Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 29, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2117090119
Keywords
alternative splicing; retinal disease model; zebrafish
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Funding
- Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa (MCIN/AEI) [CEX2020-001049-S]
- Generalitat de Catalunya through the CERCA programme
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Retinal photoreceptors have a unique transcriptomic profile, including distinct microexons and a microexon program regulated by Srrm3. Deletion of Srrm3 may lead to retinal diseases, highlighting the transcriptomic specialization and functionality of photoreceptors.
Retinal photoreceptors have a distinct transcriptomic profile compared to other neuronal subtypes, likely reflecting their unique cellular morphology and function in the detection of light stimuli by way of the ciliary outer segment. We discovered a layer of this molecular specialization by revealing that the vertebrate retina expresses the largest number of tissue-enriched microexons of all tissue types. A subset of these microexons is included exclusively in photoreceptor transcripts, particularly in genes involved in cilia biogenesis and vesicle-mediated transport. This microexon program is regulated by Srrm3, a paralog of the neural microexon regulator Srrm4. Despite the fact that both proteins positively regulate retina microexons in vitro, only Srrm3 is highly expressed in mature photoreceptors. Its deletion in zebrafish results in widespread down-regulation of microexon inclusion from early developmental stages, followed by other transcriptomic alterations, severe photoreceptor defects, and blindness. These results shed light on the transcriptomic specialization and functionality of photoreceptors, uncovering unique cell type-specific roles for Srrm3 and microexons with implications for retinal diseases.
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