Abstract
Alternative pre-mRNA splicing expands the coding capacity of eukaryotic genomes, potentially enabling a limited number of genes to govern the development of complex anatomical structures. Alternative splicing is particularly prevalent in the vertebrate nervous system, where it is required for neuronal development and function. Here, we show that photoreceptor cells, a type of sensory neuron, express a characteristic splicing program that affects a broad set of transcripts and is initiated prior to the development of the light sensing outer segments. Surprisingly, photoreceptors lack prototypical neuronal splicing factors and their splicing profile is driven to a significant degree by the Musashi 1 (MSI1) protein. A striking feature of the photoreceptor splicing program are exons that display a "switch-like" pattern of high inclusion levels in photoreceptors and near complete exclusion outside of the retina. Several ubiquitously expressed genes that are involved in the biogenesis and function of primary cilia produce highly photoreceptor specific isoforms through use of such “switch-like” exons. Our results suggest a potential role for alternative splicing in the development of photoreceptors and the conversion of their primary cilia to the light sensing outer segments.
Highlights
Vertebrate nervous systems contain numerous types of neurons with characteristic morphology, connectivity, electrophysiological properties, and neurotransmitter signatures
Vertebrates possess extraordinarily complex nervous systems that are formed by hundreds of different types of neurons
BC is a recipient of National Institute of General Medical Sciences fellowship F32GM109630
Summary
Vertebrate nervous systems contain numerous types of neurons with characteristic morphology, connectivity, electrophysiological properties, and neurotransmitter signatures. A limitation of the single cell approaches is the relatively low coverage of the transcriptome that is biased towards the 3'-end of the transcripts [6]. The depth and distribution of the reads produced by the current single cell transcriptome profiling approaches do not allow the reliable assessment of the levels of transcript isoforms produced by alternative splicing. Alternative pre-mRNA splicing is a major mechanism for generating protein diversity in vertebrates. Neurons use alternative splicing for generating protein diversity to a significantly higher degree than any other cell type [13,14]. With the exception of PTBP1, these proteins have high expression levels in neurons and are not expressed or have limited expression outside of the nervous system. PTBP1, which represses splicing of neuronal exons outside of the nervous system, is replaced by the PTBP2 in the early stages of neuronal differentiation
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