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The Musashi proteins MSI1 and MSI2 are required for photoreceptor morphogenesis and vision in mice
Jesse Sundar1, Fatimah Matalkah1, Bohye Jeong1
1Department of Biochemistry, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, West Virginia, USA.
Abstract:
The Musashi family of RNA-binding proteins is known for its role in stem-cell renewal and is a negative regulator of cell differentiation. Interestingly, in the retina, the Musashi proteins MSI1 and MSI2 are differentially expressed throughout the cycle of retinal development, with MSI2 protein displaying robust expression in the adult retinal tissue. In this study, we investigated the importance of Musashi proteins in the development and function of photoreceptor neurons in the retina. We generated a pan-retinal and rod photoreceptor neuron-specific conditional KO mouse lacking MSI1 and MSI2. Independent of the sex, photoreceptor neurons with simultaneous deletion of Msi1 and Msi2 were unable to respond to light and displayed severely disrupted photoreceptor outer segment morphology and ciliary defects. Mice lacking MSI1 and MSI2 in the retina exhibited neuronal degeneration, with complete loss of photoreceptors within 6 months. In concordance with our earlier studies that proposed a role for Musashi proteins in regulating alternative splicing, the loss of MSI1 and MSI2 prevented the use of photoreceptor-specific exons in transcripts critical for outer segment morphogenesis, ciliogenesis, and synaptic transmission. Overall, we demonstrate a critical role for Musashi proteins in the morphogenesis of terminally differentiated photoreceptor neurons. This role is in stark contrast with the canonical function of these two proteins in the maintenance and renewal of stem cells.
Insights
Musashi proteins MSI1 and MSI2 are crucial for photoreceptor neuron development and function in the retina. Loss of these RNA-binding proteins leads to vision loss and photoreceptor degeneration.
Area of Science:
- Neuroscience
- Molecular Biology
- Developmental Biology
Background:
- Musashi proteins (MSI1, MSI2) are known RNA-binding proteins involved in stem cell renewal and inhibiting differentiation.
- MSI1 and MSI2 exhibit differential expression during retinal development, with MSI2 prominent in adult retinal tissue.
Purpose of the Study:
- To investigate the role of Musashi proteins (MSI1 and MSI2) in the development and function of retinal photoreceptor neurons.
- To understand the impact of MSI1 and MSI2 loss on photoreceptor cell structure, function, and survival.
Main Methods:
- Generation of pan-retinal and rod photoreceptor neuron-specific conditional knockout (KO) mice lacking both MSI1 and MSI2.
- Analysis of photoreceptor morphology, ciliary structure, light response, and neuronal degeneration in KO mice.
Main Results:
- Simultaneous deletion of MSI1 and MSI2 in photoreceptors caused severe defects in outer segment morphology and cilia.
- Photoreceptor neurons lacking MSI1 and MSI2 were non-functional, unable to respond to light, and underwent degeneration, leading to complete photoreceptor loss within 6 months.
- Loss of MSI1 and MSI2 disrupted the alternative splicing of critical genes involved in outer segment development, ciliogenesis, and synaptic transmission.
Conclusions:
- Musashi proteins play a critical, non-canonical role in the morphogenesis and maintenance of terminally differentiated photoreceptor neurons.
- This function contrasts with their established role in stem cell renewal and differentiation regulation.
