Primary Cilium Mediated Retinal Pigment Epithelium Maturation is Retarded in Ciliopathy Patient Cells
66 Pages Posted: 6 Apr 2018 Sneak Peek Status: PublishedMore...
Primary cilia are sensory organelles that protrude from the cell membrane. Cilia defects cause ciliopathy disorders with retinal degeneration as a prominent phenotype. Here, we demonstrate that the retinal pigment epithelium (RPE), essential for photoreceptor development and function, requires a functional primary cilium for complete maturation, and RPE maturation defects in ciliopathies precede photoreceptor development. Pharmacologically enhanced ciliogenesis in wildtype induced pluripotent stem cells (iPSCs)-RPE leads to fully-mature and functional cells. Whereas, ciliopathy patient-derived iPSCs-RPE and wildtype iPSC-RPE with a knockdown of ciliary-trafficking protein remain immature, with defective apical processes, reduced functionality, and reduced adult-specific gene expression. Primary cilia proteins regulate RPE maturation by simultaneously suppressing canonical-WNT and activating PKC-δ pathways. A similar cilia-dependent maturation pathway exists in lung epithelium. Our results provide novel insights into ciliopathy-induced retinal degeneration, demonstrate a developmental role for primary cilia in epithelial maturation, and provide a method to mature iPSC-epithelial cells for clinical applications.
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