부산대학교 도서관

Mutations in the retinitis pigmentosa GTPase regulator (RPGR) protein cause one of the most common and severe forms of inherited retinal dystrophy. In spite of numerous studies, the precise function of RPGR remains unclear, as is the mechanism by which RPGR mutations cause retinal degeneration. We have analysed the function of RPGR by RNA interference-mediated translational suppression [knockdown (KD)] using a model cellular system for studying the formation, maintenance and function of primary cilia (human telomerase-immortalized retinal pigmented epithelium 1 cells). We observed that RPGR-deficient cells exhibited reduced numbers of cilia, slower cell cycle progression and impaired attachment to fibronectin, but showed no migration defects in a wound-healing assay. RPGR KD cells showed stronger actin filaments, associated with basal dysregulation of the Akt, Erk1/2, focal adhesion kinase and Src signalling pathways, as well as a 20% reduction in β1-integrin receptors at the cell surface and impaired fibronectin-induced signalling. Stronger actin filaments and impairment of the above signalling pathways suggest a common underlying mechanism for all of the cellular phenotypes observed in RPGR KD cells. Our data underline a novel function for RPGR in cilia formation and in the regulation of actin stress filaments, suggesting that, in the retina, it may regulate nascent photoreceptor disc formation by regulating actin-mediated membrane extension.