Specialization of the photoreceptor transcriptome by <i>Srrm3</i> -dependent microexons is required for outer segment maintenance and vision

Abstract

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 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 <i>Srrm3</i> and microexons with implications for retinal diseases.