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Primary Cilium Mediated Retinal Pigment Epithelium Maturation is Retarded in Ciliopathy Patient Cells

66 Pages Posted: 6 Apr 2018 Sneak Peek Status: Published

See all articles by Helen Louise May-Simera

Helen Louise May-Simera

Johannes Gutenberg University Mainz - Institute of Molecular Physiology (imP)

Qin Wan

Government of the United States of America - National Eye Institute

Balendu Shekhar Jha

Government of the United States of America - National Eye Institute

Juliet Hartford

Government of the United States of America - National Eye Institute

Vladimir Khristov

Government of the United States of America - National Eye Institute

Roba Dejene

Government of the United States of America - National Eye Institute

Justin Chang

Government of the United States of America - National Eye Institute

Sarita Patnaik

Johannes Gutenberg University Mainz - Institute of Molecular Physiology (imP)

Quanlong Lu

Government of the United States of America - National Cancer Institute

Poulomi Banerjee

Manipal Academy of Higher Education (MAHE) - School of Regenerative Medicine (SORM)

Jason Silver

Government of the United States of America - National Eye Institute

Christine Insinna-Kettenhofen

Government of the United States of America - National Cancer Institute

Dishita Patel

Government of the United States of America - National Eye Institute

Mostafa Lotfi

Government of the United States of America - National Eye Institute

May Malicdan

National Institutes of Health (NIH) - National Human Genome Research Institute

Nathan Hotaling

Government of the United States of America - National Eye Institute

Arvydas Maminishkis

Government of the United States of America - National Eye Institute

Rupa Sridharan

University of Wisconsin - Madison

Brian Brooks

Government of the United States of America - National Eye Institute

Kiyoharu Miyagishima

Government of the United States of America - National Eye Institute

Meral Gunay-Aygun

National Institutes of Health (NIH) - National Human Genome Research Institute

Rajarshi Pal

Manipal Academy of Higher Education (MAHE) - School of Regenerative Medicine (SORM)

Christopher Westlake

Government of the United States of America - National Cancer Institute

Sheldon Miller

Government of the United States of America - National Eye Institute

Ruchi Sharma

Government of the United States of America - National Eye Institute

Kapil Bharti

Government of the United States of America - National Eye Institute

More...

Abstract

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.

Suggested Citation

May-Simera, Helen Louise and Wan, Qin and Jha, Balendu Shekhar and Hartford, Juliet and Khristov, Vladimir and Dejene, Roba and Chang, Justin and Patnaik, Sarita and Lu, Quanlong and Banerjee, Poulomi and Silver, Jason and Insinna-Kettenhofen, Christine and Patel, Dishita and Lotfi, Mostafa and Malicdan, May and Hotaling, Nathan and Maminishkis, Arvydas and Sridharan, Rupa and Brooks, Brian and Miyagishima, Kiyoharu and Gunay-Aygun, Meral and Pal, Rajarshi and Westlake, Christopher and Miller, Sheldon and Sharma, Ruchi and Bharti, Kapil, Primary Cilium Mediated Retinal Pigment Epithelium Maturation is Retarded in Ciliopathy Patient Cells (2018). Available at SSRN: https://ssrn.com/abstract=3155914 or http://dx.doi.org/10.2139/ssrn.3155914
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Helen Louise May-Simera (Contact Author)

Johannes Gutenberg University Mainz - Institute of Molecular Physiology (imP)

Johann-Joachim Becher-Weg 7
Mainz, D-55128
Germany

Qin Wan

Government of the United States of America - National Eye Institute

9000 Rockville Pike
Bethesda, MD 20892
United States

Balendu Shekhar Jha

Government of the United States of America - National Eye Institute

9000 Rockville Pike
Bethesda, MD 20892
United States

Juliet Hartford

Government of the United States of America - National Eye Institute

9000 Rockville Pike
Bethesda, MD 20892
United States

Vladimir Khristov

Government of the United States of America - National Eye Institute

9000 Rockville Pike
Bethesda, MD 20892
United States

Roba Dejene

Government of the United States of America - National Eye Institute

9000 Rockville Pike
Bethesda, MD 20892
United States

Justin Chang

Government of the United States of America - National Eye Institute

9000 Rockville Pike
Bethesda, MD 20892
United States

Sarita Patnaik

Johannes Gutenberg University Mainz - Institute of Molecular Physiology (imP)

Johann-Joachim Becher-Weg 7
Mainz, D-55128
Germany

Quanlong Lu

Government of the United States of America - National Cancer Institute

9609 Medical Center Drive
Bethesda, MD 20892
United States

Poulomi Banerjee

Manipal Academy of Higher Education (MAHE) - School of Regenerative Medicine (SORM)

Manipal, Karnataka 576104
India

Jason Silver

Government of the United States of America - National Eye Institute

9000 Rockville Pike
Bethesda, MD 20892
United States

Christine Insinna-Kettenhofen

Government of the United States of America - National Cancer Institute

9609 Medical Center Drive
Bethesda, MD 20892
United States

Dishita Patel

Government of the United States of America - National Eye Institute

9000 Rockville Pike
Bethesda, MD 20892
United States

Mostafa Lotfi

Government of the United States of America - National Eye Institute

9000 Rockville Pike
Bethesda, MD 20892
United States

May Malicdan

National Institutes of Health (NIH) - National Human Genome Research Institute

Building 29, Room $a56
49 Convent Dr, MSC 4472
Bethesda, MD 20892
United States

Nathan Hotaling

Government of the United States of America - National Eye Institute

9000 Rockville Pike
Bethesda, MD 20892
United States

Arvydas Maminishkis

Government of the United States of America - National Eye Institute

9000 Rockville Pike
Bethesda, MD 20892
United States

Rupa Sridharan

University of Wisconsin - Madison

716 Langdon Street
Madison, WI 53706-1481
United States

Brian Brooks

Government of the United States of America - National Eye Institute

9000 Rockville Pike
Bethesda, MD 20892
United States

Kiyoharu Miyagishima

Government of the United States of America - National Eye Institute

9000 Rockville Pike
Bethesda, MD 20892
United States

Meral Gunay-Aygun

National Institutes of Health (NIH) - National Human Genome Research Institute

Building 29, Room $a56
49 Convent Dr, MSC 4472
Bethesda, MD 20892
United States

Rajarshi Pal

Manipal Academy of Higher Education (MAHE) - School of Regenerative Medicine (SORM)

Manipal, Karnataka 576104
India

Christopher Westlake

Government of the United States of America - National Cancer Institute

9609 Medical Center Drive
Bethesda, MD 20892
United States

Sheldon Miller

Government of the United States of America - National Eye Institute

9000 Rockville Pike
Bethesda, MD 20892
United States

Ruchi Sharma

Government of the United States of America - National Eye Institute

9000 Rockville Pike
Bethesda, MD 20892
United States

Kapil Bharti

Government of the United States of America - National Eye Institute

9000 Rockville Pike
Bethesda, MD 20892
United States

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