ADP-Ribosylation Factor-Like 2 (ARL2) regulates cilia stability and development of outer segments in rod photoreceptor neurons

Wright, Zachary C.; Loskutov, Yuriy V.; Murphy, Daniel P.; Stoilov, Peter; Pugacheva, Elena N.; Goldberg, Andrew F.X.; Ramamurthy, Visvanathan

doi:10.1038/s41598-018-35395-3

Cited by 14 publications

(19 citation statements)

References 36 publications

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“…Electroretinography, immunoblotting, and reverse transcriptase PCR were conducted using previously described protocol from our laboratory (8,24,25). Primer used for splicing analysis of photoreceptor specific exons were reported previously (8).…”

Section: Electroretinography Immunoblotting and Reverse Transcriptamentioning

confidence: 99%

The Musashi proteins MSI1 and MSI2 are required for photoreceptor morphogenesis and vision in mice

Sundar

Matalkah

Jeong

et al. 2021

Journal of Biological Chemistry

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The Musashi family of RNA-binding proteins is known for its role in stem-cell renewal and are negative regulators 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 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 photoreceptor outer segment morphology and ciliary defects. Mice lacking MSI1 and MSI2 in the retina exhibited neuronal degeneration, with complete loss of photoreceptors within six 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 OS 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.

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Section: Electroretinography Immunoblotting and Reverse Transcriptamentioning

confidence: 99%

The Musashi proteins MSI1 and MSI2 are required for photoreceptor morphogenesis and vision in mice

Sundar

Matalkah

Jeong

et al. 2021

Journal of Biological Chemistry

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“…Initial characterization was established by its interaction with ARL2, a member of the ARF-like (ADP ribosylation factor) family which are a group of small GTP-binding proteins belonging to the RAS superfamily [23–25]. A recent report using constitutively active ARL2 (Q70L mutation) in retina demonstrates a defect in outer segment morphology with rapid loss of photoreceptor function [26]. However, Arl2bp KO does not phenocopy the constitutively active Arl2 murine model, and in addition, our attempts to show this interaction in sperm or retina have been unfruitful (16).…”

Section: Discussionmentioning

confidence: 99%

Mutations in ARL2BP, a protein required for ciliary microtubule structure, cause syndromic male infertility in humans and mice

et al. 2019

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Cilia are evolutionarily conserved hair-like structures with a wide spectrum of key biological roles, and their dysfunction has been linked to a growing class of genetic disorders, known collectively as ciliopathies. Many strides have been made towards deciphering the molecular causes for these diseases, which have in turn expanded the understanding of cilia and their functional roles. One recently-identified ciliary gene is ARL2BP , encoding the ADP-Ribosylation Factor Like 2 Binding Protein. In this study, we have identified multiple ciliopathy phenotypes associated with mutations in ARL2BP in human patients and in a mouse knockout model. Our research demonstrates that spermiogenesis is impaired, resulting in abnormally shaped heads, shortened and mis-assembled sperm tails, as well as in loss of axonemal doublets. Additional phenotypes in the mouse included enlarged ventricles of the brain and situs inversus. Mouse embryonic fibroblasts derived from knockout animals revealed delayed depolymerization of primary cilia. Our results suggest that ARL2BP is required for the structural maintenance of cilia as well as of the sperm flagellum, and that its deficiency leads to syndromic ciliopathy.

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“…Electroretinography, immunoblotting, and reverse transcriptase PCR were conducted using previously described protocol from our laboratory (8,24,25).…”

Section: Electroretinography Immunoblotting and Reverse Transcriptamentioning

confidence: 99%

“…Immunofluorescence microscopy was carried out using a modified procedure in our laboratory (24,25). Briefly, eyes were enucleated, and the cornea and lens were discarded.…”

Section: Immunofluorescence Microscopymentioning

confidence: 99%

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A critical role for Musashi in photoreceptor morphogenesis and Vision

Sundar

Matalkah

Jeong

et al. 2020

Preprint

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23We previously proposed a role for the Musashi proteins, MSI1 and MSI2, in 24 photoreceptor cell development that is mediated by their ability to control alternative splicing. 25 Photoreceptors with simultaneous deletion of Msi1 and Msi2 did not respond to light, displayed 26 severely disrupted OS morphology and axonemal defects. At postnatal day 5, we observed an 27 increase in proliferating retinal progenitor cells in the knockout animals, suggesting delay in 28 photoreceptor development. The loss of Musashi prevented the use of photoreceptor-specific 29 exons in transcripts important for OS morphogenesis, ciliogenesis and synaptic transmission.30 However, deletion of the photoreceptor-specific exons in Ttc8, Cc2d2a, Cep290, Cacna2d4, and 31 Slc17a7 did not impair retinal development or visual function. We demonstrate a critical role for 32 Musashi in the morphogenesis of terminally differentiated photoreceptor neurons. This role is in 33 stark contrast with the canonical function of the two proteins in maintenance and renewal of stem 34 cells. 35 36 37 38 42Alternative splicing is particularly prevalent in vertebrate neurons and is critical for the 43 development and function of vertebrate nervous systems 2-7 . 44 We previously showed that photoreceptor neurons exploit a unique splicing program 8 . 45Motif enrichment analysis suggested that Musashi-1 (MSI1) and Musashi-2 (MSI2), promote the 46 use of photoreceptor specific exons 8 . We further showed that MSI1 is critical for utilization of 47 photoreceptor specific exon in Tetratricopeptide repeat domain protein-8 (Ttc8) 8 . In addition, 48 Musashi promotes the splicing of several photoreceptor specific exons when over-expressed in 49 cultured cells 8 . Recently, analysis of a comprehensive gene expression data set that spanned 50 multiple tissues and cell types from mice and human proved that photoreceptors utilize a unique 51 set of alternative exons that are primarily regulated by MSI1 and MSI2 9 . Furthermore, the work 52 by Ling et. al. demonstrated that Msi1 transcript levels are upregulated in the developing rod 53 photoreceptors and reach exceptionally high levels compared to all other cell types or tissues in 54 the data set. 55 The MSI1 and MSI2 proteins have two highly conserved RNA binding domains (RBDs) 56 in the N-terminal region which show close to 90% sequence identity and recognize a similar 57 UAG motif in RNA 10 . The two RBDs of MSI1 and MSI2 are followed by a less conserved C-58 terminal region which shows approximately 70% sequence identity 11 . The high degree of 59 sequence identity between the MSI1 and MSI2 results in functional redundancy between the two 60 proteins 12,13 . The canonical function of the Musashi proteins is to control mRNA translation in 61 4 the cytosol 14,15 , where they can either block or enhance translation of mRNA depending on 62 cellular context 16-21 . 63 Vertebrate photoreceptors are neurons specialized in detecting and transducing light 64 stimuli. Photoreceptors are characterized by segmented morp...

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ADP-Ribosylation Factor-Like 2 (ARL2) regulates cilia stability and development of outer segments in rod photoreceptor neurons

Cited by 14 publications

References 36 publications

The Musashi proteins MSI1 and MSI2 are required for photoreceptor morphogenesis and vision in mice

The Musashi proteins MSI1 and MSI2 are required for photoreceptor morphogenesis and vision in mice

Mutations in ARL2BP, a protein required for ciliary microtubule structure, cause syndromic male infertility in humans and mice

A critical role for Musashi in photoreceptor morphogenesis and Vision

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