TY - JOUR
T1 - Primary Cilium-Mediated Retinal Pigment Epithelium Maturation Is Disrupted in Ciliopathy Patient Cells
AU - May-Simera, Helen Louise
AU - Wan, Qin
AU - Jha, Balendu Shekhar
AU - Hartford, Juliet
AU - Khristov, Vladimir
AU - Dejene, Roba
AU - Chang, Justin
AU - Patnaik, Sarita
AU - Lu, Quanlong
AU - Banerjee, Poulomi
AU - Silver, Jason
AU - Insinna-Kettenhofen, Christine
AU - Patel, Dishita
AU - Lotfi, Mostafa
AU - Malicdan, May
AU - Hotaling, Nathan
AU - Maminishkis, Arvydas
AU - Sridharan, Rupa
AU - Brooks, Brian
AU - Miyagishima, Kiyoharu
AU - Gunay-Aygun, Meral
AU - Pal, Rajarshi
AU - Westlake, Christopher
AU - Miller, Sheldon
AU - Sharma, Ruchi
AU - Bharti, Kapil
N1 - Funding Information:
This work was supported by NEI intramural funds, NIH CRM , and NIH Common Fund grants (to K.B. and S.M.), and an Alexander von Humboldt Foundation grant (to H.L.M.-S. and S.P.). The authors thank Heinz Arnheiter, Tiziana Cogliati, and Jeffery Rubin for helpful comments and Viola Kretschmer, Alur Prasad, and Sunit Dutta for technical assistance.
Publisher Copyright:
© 2017
PY - 2018/1/2
Y1 - 2018/1/2
N2 - 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. May-Simera et al. show that primary cilia regulate the maturation and polarization of human iPSC-RPE, mouse RPE, and human iPSC-lung epithelium through canonical WNT suppression and PKCδ activation. RPE cells derived from ciliopathy patients exhibit defective structure and function. These results provide insights into ciliopathy-induced retinal degeneration.
AB - 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. May-Simera et al. show that primary cilia regulate the maturation and polarization of human iPSC-RPE, mouse RPE, and human iPSC-lung epithelium through canonical WNT suppression and PKCδ activation. RPE cells derived from ciliopathy patients exhibit defective structure and function. These results provide insights into ciliopathy-induced retinal degeneration.
KW - CEP290
KW - RPE
KW - WNT signaling
KW - apical-basal polarity
KW - cell maturation
KW - cilia
KW - ciliopathy
KW - iPS cells
KW - primary cilium
KW - retinal pigment epithelium
UR - http://www.scopus.com/inward/record.url?scp=85041662793&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041662793&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2017.12.038
DO - 10.1016/j.celrep.2017.12.038
M3 - Article
C2 - 29298421
AN - SCOPUS:85041662793
SN - 2211-1247
VL - 22
SP - 189
EP - 205
JO - Cell Reports
JF - Cell Reports
IS - 1
ER -