Abstract
Primary cilia regulate polarized protein trafficking in photoreceptors, which are dynamic and highly compartmentalized sensory neurons of retina. The ciliary protein Cep290 modulates cilia formation and is frequently mutated in syndromic and non-syndromic photoreceptor degeneration. However, the underlying mechanism of associated retinopathy is unclear. Using the Cep290 mutant mouse rd16 (retinal degeneration 16), we show that Cep290-mediated photoreceptor degeneration is associated with aberrant accumulation of its novel interacting partner Rkip (Raf-1 kinase inhibitory protein). This effect is phenocopied by morpholino-mediated depletion of cep290 in zebrafish. We further demonstrate that ectopic accumulation of Rkip leads to defective cilia formation in zebrafish and cultured cells, an effect mediated by its interaction with the ciliary GTPase Rab8A. Our data suggest that Rkip prevents cilia formation and is associated with Cep290-mediated photoreceptor degeneration. Furthermore, our results indicate that preventing accumulation of Rkip could potentially ameliorate such degeneration.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / metabolism*
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Cell Cycle Proteins
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Chlorocebus aethiops
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Cilia / genetics
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Cilia / metabolism
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Cilia / pathology
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Ciliary Motility Disorders / genetics
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Ciliary Motility Disorders / metabolism*
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Ciliary Motility Disorders / pathology
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Cytoskeletal Proteins
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HEK293 Cells
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Humans
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Mice
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Phosphatidylethanolamine Binding Protein / genetics
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Phosphatidylethanolamine Binding Protein / metabolism*
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Retinal Degeneration / genetics
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Retinal Degeneration / metabolism*
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Retinal Degeneration / pathology
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Zebrafish
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Zebrafish Proteins / genetics
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Zebrafish Proteins / metabolism*
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rab GTP-Binding Proteins / genetics
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rab GTP-Binding Proteins / metabolism
Substances
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Antigens, Neoplasm
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CEP290 protein, zebrafish
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Cell Cycle Proteins
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Cep290 protein, human
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Cep290 protein, mouse
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Cytoskeletal Proteins
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Microtubule-Associated Proteins
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Neoplasm Proteins
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Nuclear Proteins
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PEBP1 protein, human
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Phosphatidylethanolamine Binding Protein
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Rab8a protein, mouse
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Raf kinase inhibitory protein, mouse
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Zebrafish Proteins
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Rab8a protein, zebrafish
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RAB8A protein, human
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rab GTP-Binding Proteins