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.

Endocytic Control of Cellular Signaling at the Primary Cilium

“…However, the role of OCRL1 in mediating endocytic recycling of LRP2 in the zebrafish kidney pronephros appears to be independent of its ciliogenic function [99]. By contrast, in cells of the trabecular meshwork (TM) in the eye, OCRL1 was implicated in regulation of cilia-mediated intraocular pressure sensation via interaction with the ciliary mechanosensory channel TRP vanilloid 4 (TRPV4), which in turn was found to impinge on transcription of the genes encoding TNF-/, TGF-b, and GLI1 [105]. Another PI(4,5)P 2 phosphatase, INPP5E, was recently shown to promote Shh signaling by catalyzing the conversion of ciliary PI(4,5)P 2 to PI(4)P, thereby preventing aberrant ciliary accumulation of the PI(4,5)P 2 -binding protein TULP3 and its cargo GPR161 [106,107], a known negative regulator of the pathway [81] (Figure 3).…”

Differential volume regulation and calcium signaling in two ciliary body cell types is subserved by TRPV4 channels

“…It has been suggested that TRPV4 channels in anterior eye tissues such as the CB and/or trabecular meshwork might regulate IOP (18,36). Specifically, if TRPV4 channels control the "inflow" pathway by regulating steady-state release of aqueous fluid then activation, suppression, or ablation of the channel might be expected to affect steady-state IOP.…”

Role of Ocrl1 and Inpp5E in primary cilia assembly and maintenance: a phosphatidylinositol phosphatase relay system?

“…59 TRPV4 plays a role in the ciliary-dependent pressure-sensing pathways and in the regulation of the transcriptional activity of TNF-α and TGF-β1. In normal ocular trabecular meshwork (TM), an increase in pressure results in a decrease in ciliary length and an increase in transcription of TNF-α and TGF-β1.…”

“…In normal ocular trabecular meshwork (TM), an increase in pressure results in a decrease in ciliary length and an increase in transcription of TNF-α and TGF-β1. 59 Consequently, loss of Ocrl1 resulted in nonresponsiveness to an increase in intraocular pressure in the ocular TM. Ocrl1-deficient zebrafish exhibit underdeveloped eyes and brain, laterality defects, and cystic kidneys, which are characteristics seen in other ciliopathy models.…”