biostudies-literatureCiampi LEuropean Research CouncilEC | ERC | HORIZON EUROPE European Research CouncilMinisterio de Ciencia e Innovaci&amp;#x00F3;nEuropean Commission&quot;la Caixa&quot; Foundatione2117090119https://www.ebi.ac.uk/biostudies/studies/S-EPMC9303857biostudies-literatureUnknown119(29)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 <i>Srrm3</i>, a paralog of the neural microexon regulator <i>Srrm4</i>. Despite the fact that both proteins positively regulate retina microexons in vitro, only <i>Srrm3</i> is highly exProceedings of the National Academy of Sciences of the United States of AmericaSpecialization of the photoreceptor transcriptome by <i>Srrm3</i>-dependent microexons is required for outer segment maintenance and vision.PMC9303857PID2020-117011GB-I00PGC2018-101271-B-I00SEV-2016-0571-18-1LCF/BQ/DI19/11730061BFU2017-89201-PERC-CoG-LS2-101002275101002275SEV-2012-0208ERC-StG-LS2-637591BFU2017-86296-P637591MSCA-IF-2017-794629Ciampi LLopez-Blanch LCianferoni DMiravet-Verde SPermanyer JIrimia MMantica FJimenez-Delgado SRuprecht VNeuhauss SCFHead SAZang JBonnal SBanfi SSerrano LRodriguez-Marin CCarrella SfalseSpecialization of the photoreceptor transcriptome by <i>Srrm3</i>-dependent microexons is required for outer segment maintenance and vision.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 <i>Srrm3</i>, a paralog of the neural microexon regulator <i>Srrm4</i>. Despite the fact that both proteins positively regulate retina microexons in vitro, only <i>Srrm3</i> is highly ex2022-01-01T00:00:00Z2022 Jul2025-04-19T23:07:59.089Z2025-04-19T23:07:59.089ZS-EPMC93038573585830610.1073/pnas.2117090119