Specialization of the photoreceptor transcriptome bySrrm3-dependent microexons is required for outer segment maintenance and vision

Abstract

Retinal photoreceptors differ in their transcriptomic profiles from other neuronal subtypes, likely as a reflection of their unique cellular morphology and function in the detection of light thorough the ciliary outer segment. We discovered a new 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 in vesicle-mediated transport. This microexon program is regulated by Srrm3, a paralog of the neural microexon regulator Srrm4. Despite both proteins positively regulate retina microexons in vitro, only Srrm3 is highly expressed in mature photoreceptors and its deletion in zebrafish results in widespread downregulation of microexon inclusion, severe photoreceptor alterations and blindness. These results shed light into photoreceptor's transcriptomic specialization and functionality, uncovering new cell type-specific roles for Srrm3 and microexons with implication for retinal diseases.

A highly conserved neuronal microexon in DAAM1 controls actin dynamics, RHOA/ROCK signaling, and memory formation

“…RNA-seq data from human HEK293 cells overexpressing human SRRM4 (Torres-Méndez el al. 2019), mouse N2A cells upon Srrm3/4 knockdown (Conatopoulos-Pournatzis et al 2018), and zebrafish retinae extracted from Srrm3 KO 5 days post fertilization larvae (Ciampi et al 2022).…”

“…To investigate the regulation of Daam1-MIC by SRRM3/4 (Fig. 1i), we used data from human HEK293 cells overexpressing human SRRM4 (GEO: GSE112600 (Torres-Méndez et al 2019)), mouse N2A cells upon Srrm3/4 knockdown (SRA: PRJNA47491 (Gonatopoulos-Pournatzis et al 2018)), and zebrafish retinae extracted from Srrm3 KO 5 days post fertilization larvae (GEO: GSE180781 (Ciampi et al 2022)). Crystal Structure of human DAAM1 FH2 domain (2z6e.pdb) was used to model the mice Daam1 FH2 domain with and without microexon using Robetta (http://new.robetta.org/) (Fig.…”

The Musashi proteins are post-transcriptional activators of protein expression and alternative 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 that either cooperate with Musashi (PCBP2) or promote the splicing of independent sets of exons (SRRM3) (Ciampi et al, 2021; Ling et al, 2020).…”

Control of pancreatic islet function and glucose homeostasis by a novel microexon program misregulated in type 2 diabetes

“…Gene Ontology (GO) analyses of IsletMICs were performed gprofiler2 R package (Kolberg et al, 2020), with custom annotations and gene backgrounds. Human GO annotations were obtained from 33 . For GO analysis of human IsletMICs, we provided as a custom gene background all genes harboring at least one splicing event of any type from vast-tools passing the same filtering criteria required in the analysis described above using the Get_Tissue_Specific_AS .…”

“…Gene Ontology (GO) analyses of IsletMICs were performed gprofiler2 R package (Kolberg et al, 2020), with custom annotations and gene backgrounds. Human GO annotations were obtained from 33 .…”