The Musashi 1 Controls the Splicing of Photoreceptor-Specific Exons in the Vertebrate Retina

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.

Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets

“…For example, it may be useful to transiently enhance Musashi function when enlarging stem or progenitor pools for therapeutic purposes, such as bone marrow replacement. As other examples, MSI1 is induced as part of the damage response process in models for arthritis(85), elevated in atherosclerotic plaques(86), and critical for survival of photoreceptors and appropriate cell function in the retina (71,87). Clearly, more work is needed to refine the role of MSI proteins in these and other tissues, with the goal of ameliorating pathologic conditions.…”

“…Connecting Musashi proteins to control of miRS, discrete LIN28-binding motif has been identified in the C-terminus of MSI1 (9): while this motif is absent in MSI2, recent studies have nevertheless shown biological activity of MSI2 in regulating Lin28A (23,61). Additionally, both MSI1 and MSI2 have been described to regulate alternative splicing in mouse retinal photoreceptor and neural stem cells, with mechanisms still to be exactly defined (54,71). Understanding how the protein structure and signaling downstream of MSI1 and MSI2 are linked to their function in different cellular contexts remains an important area for future work.…”

Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies

“…This implies that CWC27 exerts functions essential for both early tissue development and later functional maintenance. Furthermore, the non-syndromic RP-affected case subject in family 3 also shows that the mature retina, with a high rate of protein turnover and extensive alternative splicing, [55][56][57] is particularly vulnerable to perturbations of spliceosome assembly and functions. In addition, we observed some family-specific symptoms outside the above-mentioned two phenotypic domains, such as ectodermal defects in family 4 and internal organ anomalies in families 5 and 6, suggesting that CWC27 may play important roles in additional tissues.…”

Stem Cells, Cancer, and MUSASHI in Blood and Guts

“…More recent studies however suggest the molecular function of MSI proteins may be far more complex than translational inhibition. The Msi family has been implicated in controlling polyadenylation of specific mRNAs in Xenopus oocytes, alternative splicing in photoreceptor cells and neurons, and message stabilization as well as translational potentiation by MSI has been suggested 10–14 . Despite our lack of understanding regarding the molecular underpinnings of target regulation by MSI proteins, their importance in governing stem cell activity and oncogenesis has become increasingly clear from studies focusing on the hematopoietic system and intestinal epithelium- two high-turnover tissues with well-defined stem cell compartments prone to oncogenic transformation.…”