Compensatory Role of Inositol 5-Phosphatase INPP5B to OCRL in Primary Cilia Formation in Oculocerebrorenal Syndrome of Lowe

Luo, Na; Kumar, Akhilesh; Conwell, Michael; Weinreb, Robert N.; Anderson, Ryan M.; Sun, Yang

doi:10.1371/journal.pone.0066727

Cited by 36 publications

(37 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Decreased 5-phosphatase activity is demonstrated in fibroblasts from Lowe patients as well as a two-to threefold elevated ratio of PI(4,5)P 2 : PI(4)P (3). We and others have recently identified a novel link between OCRL and primary cilia (4)(5)(6)(7).…”

mentioning

confidence: 87%

Primary cilia signaling mediates intraocular pressure sensation

Luo

Conwell

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

106

View full text Add to dashboard Cite

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.

show abstract

mentioning

confidence: 87%

Primary cilia signaling mediates intraocular pressure sensation

Luo

Conwell

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

106

View full text Add to dashboard Cite

show abstract

“…In C. elegans , a phosphoinositide 5-phosphatase, CIL-1, controls PI(3)P levels and the ciliary localization of PKD-2, suggesting that phosphoinositides can participate in ciliary protein trafficking (Bae et al 2009). In mammals, three phosphoinositide 5-phosphatases, Ocrl, Inpp5b and Inpp5e, can localize to cilia (Jacoby et al 2009; Bielas et al 2009; Luo et al 2012 and 2013). Mutations in human INPP5E can cause the ciliopathy Joubert syndrome, and knockout of mouse Inpp5e results in phenotypes characteristic of ciliopathies, including cystic kidneys and polydactyly (Jacoby et al 2009; Bielas et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Phosphoinositides Regulate Ciliary Protein Trafficking to Modulate Hedgehog Signaling

et al. 2015

View full text Add to dashboard Cite

SUMMARY Primary cilia interpret vertebrate Hedgehog (Hh) signals. Why cilia are essential for signaling is unclear. One possibility is that some forms of signaling require a distinct membrane lipid composition, found at cilia. We found that the ciliary membrane contains a particular phosphoinositide, PI(4)P, whereas a different phosphoinositide, PI(4,5)P2, is restricted to the membrane of the ciliary base. This distribution is created by Inpp5e, a ciliary phosphoinositide 5-phosphatase. Without Inpp5e, ciliary PI(4,5)P2 levels are elevated and Hh signaling is disrupted. Inpp5e limits the ciliary levels of inhibitors of Hh signaling, including Gpr161 and the PI(4,5)P2-binding protein Tulp3. Increasing ciliary PI(4,5)P2 levels or conferring the ability to bind PI(4)P on Tulp3 increases the ciliary localization of Tulp3. Lowering Tulp3 in cells lacking Inpp5e reduces ciliary Gpr161 levels and restores Hh signaling. Therefore, Inpp5e regulates ciliary membrane phosphoinositide composition, and Tulp3 reads out ciliary phosphoinositides to control ciliary protein localization, enabling Hh signaling.

show abstract

“…80 Indeed, KD of Inpp5B in zebrafish resulted in edema, body asymmetry, kinked tail, and microphthalmia, which are classical characteristics observed in ciliary disease zebrafish models. These animals showed defective ciliary formation in the Kupffer's vesicle, with lesser and shorter cilia in comparison to controls.…”

mentioning

confidence: 99%

“…80 In addition, Ocrl1 and Inpp5B morpholino coinjected fish showed more severe phenotypes suggesting that they play a synergistic role in the ciliary function in zebrafish. 80 Studies using LS fibroblast also showed partial rescue of the ciliogenesis phenotype upon overexpression of Inpp5B.…”

mentioning

confidence: 99%

“…These animals showed defective ciliary formation in the Kupffer's vesicle, with lesser and shorter cilia in comparison to controls. 80 These defects were rescued upon reintroduction of Inpp5B mRNA, thereby establishing a ciliary role for Inpp5B. 80 In addition, Ocrl1 and Inpp5B morpholino coinjected fish showed more severe phenotypes suggesting that they play a synergistic role in the ciliary function in zebrafish.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Madhivanan¹,

Ramadesika²,

Aguilar

2016

RRB

View full text Add to dashboard Cite

Abstract:The primary cilium (PC) is a plasma membrane-derived structure of great importance for cell and organismal physiology. Indeed, abnormalities in assembly or function of the PC trigger the onset of a group of genetic diseases collectively known as ciliopathies. In recent years, it has become evident that the integrity and function of the PC depends substantially on signaling elements such as phosphoinositides (PI) and their regulators. Because phospholipids such as PI(4,5)P 2 constitute recruitment platforms for cytoskeleton, signaling, and trafficking machinery, control over their levels is critical for PC function. Although information about phosphoinositol phosphate (PIP) kinases in the PC is scarce, a growing body of evidence supports a role for PIP phosphatases in cilia assembly/maintenance. Indeed, deficiencies in two 5′ PIP phosphatases, Inpp5E and Ocrl1, are clearly linked to ciliopathies like Joubert/MORM syndromes, or ciliopathy-associated dise ases like Lowe syndrome. Here, we review the unique roles of these proteins and their specific site of action for ensuring ciliary integrity. Further, we discuss the possibility that a phosphatase relay system able to pass PI control from a preciliary to an intraciliary compartment is in place to ensure PC integrity/function.

show abstract

Compensatory Role of Inositol 5-Phosphatase INPP5B to OCRL in Primary Cilia Formation in Oculocerebrorenal Syndrome of Lowe

Cited by 36 publications

References 44 publications

Primary cilia signaling mediates intraocular pressure sensation

Primary cilia signaling mediates intraocular pressure sensation

Phosphoinositides Regulate Ciliary Protein Trafficking to Modulate Hedgehog Signaling

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

Contact Info

Product

Resources

About