Unique transcriptomes of sensory and non-sensory neurons: insights from Splicing Regulatory States

Abstract

Alternative Splicing (AS) programs serve as instructive signals of cell type specificity, particularly within the brain, which comprises dozens of molecularly and functionally distinct cell types. Among them, retinal photoreceptors stand out due to their unique transcriptome, making them a particularly well-suited system for studying how AS shapes cell type-specific molecular functions. Here, we use the Splicing Regulatory State (SRS) as a novel framework to discuss the splicing factors governing the unique AS pattern of photoreceptors, and how this pattern may aid in the specification of their highly specialized sensory cilia. In addition, we discuss how other sensory cells with ciliated structures, for which data is much scarcer, also rely on specific SRSs to implement a proteome specialized in the detection of sensory stimuli. By reviewing the general rules of cell type- and tissue-specific AS programs, firstly in the brain and subsequently in specialized sensory neurons, we propose a novel paradigm on how SRSs are established and how they can diversify. Finally, we illustrate how SRSs shape the outcome of mutations in splicing factors to produce cell type-specific phenotypes that can lead to various human diseases.

A Precision Therapy Approach for Retinitis Pigmentosa 11 Using Splice-Switching Antisense Oligonucleotides to Restore the Open Reading Frame of PRPF31

“…Although splicing factors are essential in most cells, mutations in PRPF31 and other splicing factor genes do not impair splicing in all tissues and are currently known to only affect the retina. Restriction of symptoms to the retina may reflect the exceptionally high demand for mRNA processing, particularly in photoreceptors and retinal pigment epithelium (RPE), and the reliance on alternative splicing in these cell types [ 6 , 7 ] suggesting a critical role of pre-mRNA splicing in retinal homeostasis and pathogenesis in retinal dystrophy. The mechanism leading to the disease phenotypes for PRPF31 -associated RP appears to be predominantly haploinsufficiency [ 8 , 9 ].…”

Disentangling the splicing factor programs underlying complex molecular phenotypes

“…Splicing factor activities have been typically inferred based on the presence of activating and inactivating somatic mutations or differential gene expression [2][3][4][5] . However, these represent just two of the many mechanisms contributing to splicing factor activity modulation.…”