Primary cilia signaling mediates intraocular pressure sensation
| Autor: | Robert N. Weinreb, Alexander G. Obukhov, Clark D. Wells, Karen M. Joos, Yang Sun, Carlo Iomini, Christine Insinna Kettenhofen, Na Luo, Michael Conwell, Dan F. Spandau, Timothy W. Corson, Christopher J. Westlake, Louis B. Cantor, Xingjuan Chen |
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| Rok vydání: | 2014 |
| Předmět: |
Male
TRPV4 medicine.medical_specialty Mechanotransduction genetic structures Knockout Oculocerebrorenal syndrome Hydrostatic pressure Sensation TRPV Cation Channels Biology Inbred C57BL Mechanotransduction Cellular Mice Trabecular Meshwork Transforming Growth Factor beta Internal medicine Cadaver medicine Animals Humans Cilia Child Intraocular Pressure Mice Knockout Multidisciplinary Mechanosensation Tumor Necrosis Factor-alpha Cilium Biological Sciences medicine.disease eye diseases Phosphoric Monoester Hydrolases Cell biology Mice Inbred C57BL Oculocerebrorenal Syndrome Endocrinology medicine.anatomical_structure OCRL Cellular sense organs Trabecular meshwork |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 111, iss 35 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1323292111 |
| Popis: | 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 how the 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. |
| Databáze: | OpenAIRE |
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