Transcriptomic determinants of vertebrate photoreceptors and other sensory cells

Resum

The nervous system comprises an immense number of cells that serve highly specialized roles. Accordingly, they possess unique morphological and functional attributes, greatly shaped by specific Alternative Splicing (AS) and Gene Expression (GE) patterns. 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 through 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. 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, severe photoreceptor defects and blindness. Since this microexon program involves genes of the photoreceptor cilium, we explored whether other ciliated sensory cells display such specialized transcriptomes, which is not the case. However, multi-layer RNA-seq analysis revealed that cilia in olfactory neurons diverge from those of other ciliated sensory cells by activating a gene network, enriched for motile cilia genes, that are highly expressed in spermatocytes and regulated by Rfx3. In summary, our results shed light into the transcriptomic specialization and functionality of cilia in sensory cells, uncovering new cell-type specific roles for many genes with implication for a wide spectrum of human diseases.