[PDF][PDF] Primary cilium-mediated retinal pigment epithelium maturation is disrupted in ciliopathy patient cells

HL May-Simera, Q Wan, BS Jha, J Hartford, V Khristov… - Cell reports, 2018 - cell.com
HL May-Simera, Q Wan, BS Jha, J Hartford, V Khristov, R Dejene, J Chang, S Patnaik, Q Lu
Cell reports, 2018cell.com
Primary cilia are sensory organelles that protrude from the cell membrane. Defects in the
primary cilium 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 that RPE maturation defects in ciliopathies precede photoreceptor
degeneration. Pharmacologically enhanced ciliogenesis in wild-type induced pluripotent …
Summary
Primary cilia are sensory organelles that protrude from the cell membrane. Defects in the primary cilium 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 that RPE maturation defects in ciliopathies precede photoreceptor degeneration. Pharmacologically enhanced ciliogenesis in wild-type induced pluripotent stem cells (iPSC)-RPE leads to fully mature and functional cells. In contrast, ciliopathy patient-derived iPSC-RPE and iPSC-RPE with a knockdown of ciliary-trafficking protein remain immature, with defective apical processes, reduced functionality, and reduced adult-specific gene expression. Proteins of the primary cilium regulate RPE maturation by simultaneously suppressing canonical WNT and activating PKCδ pathways. A similar cilium-dependent maturation pathway exists in lung epithelium. Our results provide 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.
cell.com