Specialization of the photoreceptor transcriptome by Srrm3 -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 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.

miR ‐181a/b downregulation: a mutation‐independent therapeutic approach for inherited retinal diseases

“…Count of nuclei in ONL was performed on three eyes/genotype (at least two sections per eye) at p30. Only sections in which the optic nerve was contained were used, and two images from each section were photographed under a Leica DM‐5500 microscope, with the objective Leica ∞/0.17/D, HCX PL FLUOTAR, 40×/0.75 that acquires an area of 0.31 mm 2 , in comparable regions equidistant from the optic nerve head (Barbato et al , 2017; Karali et al , 2020; Ciampi et al , 2022; Intartaglia et al , 2022). The acquired images were used for nuclei counts.…”

The Musashi proteins direct post-transcriptional control of protein expression and alternate exon splicing in vertebrate photoreceptors

“…This leaves a sizable population of photoreceptor-specific exons that rely on other factors for their splicing. Recent studies have highlighted two such factors, PCBP2 and SRRM3, that can either act independently or cooperate with Musashi to promote splicing of alternative exons in photoreceptors 42 , 45 .…”

The Deubiquitinating Enzyme USP48 Interacts with the Retinal Degeneration-Associated Proteins UNC119a and ARL3

“…Some examples are RPGR and BBS8 , both causative of non-syndromic retinal ciliopathies when their mutations map in retina-specific exons exclusively present in photoreceptor isoforms [ 51 , 52 ]. Interestingly, a recent study showed that retina-enriched microexons are particularly present in genes involved in vesicle-mediated transport, cilium assembly, and ciliary trafficking [ 53 ]. USP48 has many annotated isoforms, but only the full-length protein has been studied so far.…”