Primary cilia signaling mediates intraocular pressure sensation.

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 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.

• Authors: Na Luo, Michael D Conwell, Xingjuan Chen, Christine Insinna Kettenhofen, Christopher J Westlake, Louis B Cantor, Clark D Wells, Robert N Weinreb, Timothy W Corson, Dan F Spandau, Karen M Joos, Carlo Iomini, Alexander G Obukhov, Yang Sun
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 35 Pg. 12871-6 (Sep 02 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25143588 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• TRPV Cation Channels
• TRPV4 protein, human
• Transforming Growth Factor beta
• Trpv4 protein, mouse
• Tumor Necrosis Factor-alpha
• Phosphoric Monoester Hydrolases
• OCRL protein, human
• Ocrl protein, mouse

Topics

• Animals
• Cadaver
• Child
• Cilia (metabolism)
• Humans
• Intraocular Pressure (physiology)
• Male
• Mechanotransduction, Cellular (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Oculocerebrorenal Syndrome (metabolism, physiopathology)
• Phosphoric Monoester Hydrolases (metabolism)
• Sensation (physiology)
• TRPV Cation Channels (metabolism)
• Trabecular Meshwork (cytology, metabolism)
• Transforming Growth Factor beta (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)