Primary Cilium-Mediated Retinal Pigment Epithelium Maturation Is Disrupted in Ciliopathy Patient Cells

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 an...

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Main Authors:	Helen Louise May-Simera, Qin Wan, Balendu Shekhar Jha, Juliet Hartford, Vladimir Khristov, Roba Dejene, Justin Chang, Sarita Patnaik, Quanlong Lu, Poulomi Banerjee, Jason Silver, Christine Insinna-Kettenhofen, Dishita Patel, Mostafa Lotfi, May Malicdan, Nathan Hotaling, Arvydas Maminishkis, Rupa Sridharan, Brian Brooks, Kiyoharu Miyagishima, Meral Gunay-Aygun, Rajarshi Pal, Christopher Westlake, Sheldon Miller, Ruchi Sharma, Kapil Bharti
Format:	Article
Language:	English
Published:	Elsevier 2018-01-01
Series:	Cell Reports
Online Access:	http://www.sciencedirect.com/science/article/pii/S2211124717318478

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record_format	Article
spelling	doaj-bfaae5556aaf4f70affe565c4099f9ee2020-11-25T01:32:30ZengElsevierCell Reports2211-12472018-01-01221189205Primary Cilium-Mediated Retinal Pigment Epithelium Maturation Is Disrupted in Ciliopathy Patient CellsHelen Louise May-Simera0Qin Wan1Balendu Shekhar Jha2Juliet Hartford3Vladimir Khristov4Roba Dejene5Justin Chang6Sarita Patnaik7Quanlong Lu8Poulomi Banerjee9Jason Silver10Christine Insinna-Kettenhofen11Dishita Patel12Mostafa Lotfi13May Malicdan14Nathan Hotaling15Arvydas Maminishkis16Rupa Sridharan17Brian Brooks18Kiyoharu Miyagishima19Meral Gunay-Aygun20Rajarshi Pal21Christopher Westlake22Sheldon Miller23Ruchi Sharma24Kapil Bharti25Institute of Molecular Physiology, Johannes-Gutenberg University, Mainz, GermanyNational Eye Institute, NIH, Bethesda, MD, USANational Eye Institute, NIH, Bethesda, MD, USANational Eye Institute, NIH, Bethesda, MD, USANational Eye Institute, NIH, Bethesda, MD, USANational Eye Institute, NIH, Bethesda, MD, USANational Eye Institute, NIH, Bethesda, MD, USAInstitute of Molecular Physiology, Johannes-Gutenberg University, Mainz, GermanyNational Cancer Institute, NIH, Frederick, MD, USASchool of Regenerative Medicine, Manipal University, Bangalore, IndiaNational Eye Institute, NIH, Bethesda, MD, USANational Cancer Institute, NIH, Frederick, MD, USANational Eye Institute, NIH, Bethesda, MD, USANational Eye Institute, NIH, Bethesda, MD, USANational Human Genome Research Institute, NIH, Bethesda, MD, USANational Eye Institute, NIH, Bethesda, MD, USANational Eye Institute, NIH, Bethesda, MD, USAUniversity of Wisconsin, Madison, WI, USANational Eye Institute, NIH, Bethesda, MD, USANational Eye Institute, NIH, Bethesda, MD, USANational Human Genome Research Institute, NIH, Bethesda, MD, USASchool of Regenerative Medicine, Manipal University, Bangalore, IndiaNational Cancer Institute, NIH, Frederick, MD, USANational Eye Institute, NIH, Bethesda, MD, USANational Eye Institute, NIH, Bethesda, MD, USANational Eye Institute, NIH, Bethesda, MD, USA; Corresponding authorSummary: 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. Keywords: retinal pigment epithelium, RPE, ciliopathy, cell maturation, iPS cells, primary cilium, WNT signaling, apical-basal polarity, CEP290, ciliahttp://www.sciencedirect.com/science/article/pii/S2211124717318478
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Helen Louise May-Simera Qin Wan Balendu Shekhar Jha Juliet Hartford Vladimir Khristov Roba Dejene Justin Chang Sarita Patnaik Quanlong Lu Poulomi Banerjee Jason Silver Christine Insinna-Kettenhofen Dishita Patel Mostafa Lotfi May Malicdan Nathan Hotaling Arvydas Maminishkis Rupa Sridharan Brian Brooks Kiyoharu Miyagishima Meral Gunay-Aygun Rajarshi Pal Christopher Westlake Sheldon Miller Ruchi Sharma Kapil Bharti
spellingShingle	Helen Louise May-Simera Qin Wan Balendu Shekhar Jha Juliet Hartford Vladimir Khristov Roba Dejene Justin Chang Sarita Patnaik Quanlong Lu Poulomi Banerjee Jason Silver Christine Insinna-Kettenhofen Dishita Patel Mostafa Lotfi May Malicdan Nathan Hotaling Arvydas Maminishkis Rupa Sridharan Brian Brooks Kiyoharu Miyagishima Meral Gunay-Aygun Rajarshi Pal Christopher Westlake Sheldon Miller Ruchi Sharma Kapil Bharti Primary Cilium-Mediated Retinal Pigment Epithelium Maturation Is Disrupted in Ciliopathy Patient Cells Cell Reports
author_facet	Helen Louise May-Simera Qin Wan Balendu Shekhar Jha Juliet Hartford Vladimir Khristov Roba Dejene Justin Chang Sarita Patnaik Quanlong Lu Poulomi Banerjee Jason Silver Christine Insinna-Kettenhofen Dishita Patel Mostafa Lotfi May Malicdan Nathan Hotaling Arvydas Maminishkis Rupa Sridharan Brian Brooks Kiyoharu Miyagishima Meral Gunay-Aygun Rajarshi Pal Christopher Westlake Sheldon Miller Ruchi Sharma Kapil Bharti
author_sort	Helen Louise May-Simera
title	Primary Cilium-Mediated Retinal Pigment Epithelium Maturation Is Disrupted in Ciliopathy Patient Cells
title_short	Primary Cilium-Mediated Retinal Pigment Epithelium Maturation Is Disrupted in Ciliopathy Patient Cells
title_full	Primary Cilium-Mediated Retinal Pigment Epithelium Maturation Is Disrupted in Ciliopathy Patient Cells
title_fullStr	Primary Cilium-Mediated Retinal Pigment Epithelium Maturation Is Disrupted in Ciliopathy Patient Cells
title_full_unstemmed	Primary Cilium-Mediated Retinal Pigment Epithelium Maturation Is Disrupted in Ciliopathy Patient Cells
title_sort	primary cilium-mediated retinal pigment epithelium maturation is disrupted in ciliopathy patient cells
publisher	Elsevier
series	Cell Reports
issn	2211-1247
publishDate	2018-01-01
description	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. : 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. Keywords: retinal pigment epithelium, RPE, ciliopathy, cell maturation, iPS cells, primary cilium, WNT signaling, apical-basal polarity, CEP290, cilia
url	http://www.sciencedirect.com/science/article/pii/S2211124717318478
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Primary Cilium-Mediated Retinal Pigment Epithelium Maturation Is Disrupted in Ciliopathy Patient Cells

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