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Takahisa Furukawa, Yoshihiro Omori, Taro Chaya, Kimiko Katoh, Naoko Kajimura, Shigeru Sato, Shinji Ueno, Toshiyuki Koyasu, Mineo Kondo; Negative Regulation Of Ciliary Length By Ciliary Kinase Mak Is Essential For Retinal Photoreceptor Survival. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1822.
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© ARVO (1962-2015); The Authors (2016-present)
Cilia function as cell sensors in many organs and their disorders are referred to as ciliopathies. While ciliary components and transport machinery have been well studied, molecular regulatory mechanisms controlling ciliary length remain unknown. The Chlamydomonas LF4 mutant shows a long-flagella phenotype. LF4 encodes a protein highly similar to mammalian Mak kinase. Mak was first identified as a gene highly expressed in testicular germ cell. Spermatogenesis of Mak knockout (KO) mouse is intact. In addition to expression in the testis, Mak is also expressed in the retina. However, the molecular function of Mak in the retina has been unknown. We investigated a function of Mak in the mouse retina.
We performed immunostaining of retinal sections using an anti-Mak antibody and analyzed the Mak KO retina. To investigate the regulatory mechanisms of ciliary length by Mak, we established a cultured cell system in which NIH3T3 fibroblast cells develop cilia at a high frequency, and performed overexpression study of Mak and RP1.
Mak was localized both in the connecting cilia and outer segment axonemes of both rod and cone photoreceptor cells. In the Mak-null retina, photoreceptors exhibit elongated cilia and progressive degeneration. We observed accumulation of IFT88 and IFT57, expansion of Kif3a and acetylated αlpha-tubulin signals in Mak-null photoreceptor cilia. We found abnormal rhodopsin accumulation in the Mak-null photoreceptor cell bodies at P14. In addition, overexpression of RP1, a microtubule-associated protein localized in outer segment axonemes, induced ciliary elongation, and Mak coexpression rescued excessive ciliary elongation by RP1. The RP1 N-terminal portion induces both ciliary elongation and microtubule acetylation, and is phosphorylated by Mak.
We show that ciliary kinase Mak is essential for developing proper length of the photoreceptor cilia. Our results suggest that Mak and RP1 antagonistically regulate proper ciliary length and ciliary subcompartmentalization, and that dysregulation of these processes results in photoreceptor degeneration.
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