Primary cilia signaling mediates intraocular pressure sensation

Na Luo, Michael D. Conwell, Xingjuan Chen, Christine Insinna Kettenhofen, Christopher J. Westlake, Louis Cantor, Clark Wells, Robert N. Weinreb, Timothy Corson, Dan Spandau, Karen M. Joos, Carlo Iomini, Alexander Obukhov, Yang Sun

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Lowe syndrome is a rare X-linked congenital disease that presents with congenital cataracts and glaucoma, as well as renal and cerebral dysfunction. OCRL, an inositol polyphosphate 5-phosphatase, is mutated in Lowe syndrome. We previously showed that OCRL is involved in vesicular trafficking to the primary cilium. Primary cilia are sensory organelles on the surface of eukaryotic cells that mediate mechanotransduction in the kidney, brain, and bone. However, their potential role in the trabecular meshwork (TM) in the eye, which regulates intraocular pressure, is unknown. Here, we show that TM cells, which are defective in glaucoma, have primary cilia that are critical for response to pressure changes. Primary cilia in TM cells shorten in response to fluid flow and elevated hydrostatic pressure, and promote increased transcription of TNF-α, TGF-β, and GLI1 genes. Furthermore, OCRL is found to be required for primary cilia to respond to pressure stimulation. The interaction of OCRL with transient receptor potential vanilloid 4 (TRPV4), a ciliary mechanosensory channel, suggests that OCRL may act through regulation of this channel. A novel disease-causing OCRL allele prevents TRPV4-mediated calcium signaling. In addition, TRPV4 agonist GSK 1016790A treatment reduced intraocular pressure in mice; TRPV4 knockout animals exhibited elevated intraocular pressure and shortened cilia. Thus, mechanotransduction by primary cilia in TM cells is implicated in howthe eye senses pressure changes and highlights OCRL and TRPV4 as attractive therapeutic targets for the treatment of glaucoma. Implications of OCRL and TRPV4 in primary cilia function may also shed light on mechanosensation in other organ systems.

Original languageEnglish
Pages (from-to)12871-12876
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number35
DOIs
StatePublished - Sep 2 2014

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Cilia
Intraocular Pressure
TRPV Cation Channels
Trabecular Meshwork
Oculocerebrorenal Syndrome
Glaucoma
Pressure
Kidney
Hydrostatic Pressure
Calcium Signaling
Eukaryotic Cells
Organelles
Cataract
Alleles
Bone and Bones
Brain
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Primary cilia signaling mediates intraocular pressure sensation. / Luo, Na; Conwell, Michael D.; Chen, Xingjuan; Kettenhofen, Christine Insinna; Westlake, Christopher J.; Cantor, Louis; Wells, Clark; Weinreb, Robert N.; Corson, Timothy; Spandau, Dan; Joos, Karen M.; Iomini, Carlo; Obukhov, Alexander; Sun, Yang.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 35, 02.09.2014, p. 12871-12876.

Research output: Contribution to journalArticle

Luo, Na ; Conwell, Michael D. ; Chen, Xingjuan ; Kettenhofen, Christine Insinna ; Westlake, Christopher J. ; Cantor, Louis ; Wells, Clark ; Weinreb, Robert N. ; Corson, Timothy ; Spandau, Dan ; Joos, Karen M. ; Iomini, Carlo ; Obukhov, Alexander ; Sun, Yang. / Primary cilia signaling mediates intraocular pressure sensation. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 35. pp. 12871-12876.
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AU - Conwell, Michael D.

AU - Chen, Xingjuan

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AU - Wells, Clark

AU - Weinreb, Robert N.

AU - Corson, Timothy

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AU - Joos, Karen M.

AU - Iomini, Carlo

AU - Obukhov, Alexander

AU - Sun, Yang

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AB - Lowe syndrome is a rare X-linked congenital disease that presents with congenital cataracts and glaucoma, as well as renal and cerebral dysfunction. OCRL, an inositol polyphosphate 5-phosphatase, is mutated in Lowe syndrome. We previously showed that OCRL is involved in vesicular trafficking to the primary cilium. Primary cilia are sensory organelles on the surface of eukaryotic cells that mediate mechanotransduction in the kidney, brain, and bone. However, their potential role in the trabecular meshwork (TM) in the eye, which regulates intraocular pressure, is unknown. Here, we show that TM cells, which are defective in glaucoma, have primary cilia that are critical for response to pressure changes. Primary cilia in TM cells shorten in response to fluid flow and elevated hydrostatic pressure, and promote increased transcription of TNF-α, TGF-β, and GLI1 genes. Furthermore, OCRL is found to be required for primary cilia to respond to pressure stimulation. The interaction of OCRL with transient receptor potential vanilloid 4 (TRPV4), a ciliary mechanosensory channel, suggests that OCRL may act through regulation of this channel. A novel disease-causing OCRL allele prevents TRPV4-mediated calcium signaling. In addition, TRPV4 agonist GSK 1016790A treatment reduced intraocular pressure in mice; TRPV4 knockout animals exhibited elevated intraocular pressure and shortened cilia. Thus, mechanotransduction by primary cilia in TM cells is implicated in howthe eye senses pressure changes and highlights OCRL and TRPV4 as attractive therapeutic targets for the treatment of glaucoma. Implications of OCRL and TRPV4 in primary cilia function may also shed light on mechanosensation in other organ systems.

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