A critical role for MSI1 and MSI2 in photoreceptor morphogenesis

Musashi family of RNA-binding proteins are known for their role in stem-cell renewal and are negative regulators of cell differentiation. Interestingly, in the retina, Musashi proteins, MSI1 and MSI2 are differentially expressed throughout the cycle of retinal development including robust expression in the adult retinal tissue. To study the role of Musashi proteins in the retina, we generated a pan-retinal and rod photoreceptor neuron specific conditional knockout mouse lacking MSI1 and MSI2. Independent of sex, photoreceptor neurons with simultaneous deletion of Msi1 and Msi2 were unable to respond to light and displayed severely disrupted OS morphology and ciliary defects. The retina lacking Musashi exhibited neuronal degeneration with complete loss of photoreceptors by six months. In concordance with our earlier studies that proposed a role for Musashi in regulating alternative splicing, the loss of Musashi prevented the use of photoreceptor-specific exons in transcripts critical for OS morphogenesis, ciliogenesis and synaptic transmission. Overall, we demonstrate a critical role for Musashi in the morphogenesis of terminally differentiated photoreceptor neurons. This role is in stark contrast with the canonical function of these two proteins in maintenance and renewal of stem cells.