<scp>OCRL1</scp>Modulates Cilia Length in Renal Epithelial Cells

Rbaibi, Youssef; Cui, Shanshan; Mo, Di; Carattino, Marcelo D.; Rohatgi, Rajeev; Satlin, Lisa M.; Szalinski, Christina M.; Swanhart, Lisa M.; Fölsch, Heike; Hukriede, Neil A.; Weisz, Ora A.

doi:10.1111/j.1600-0854.2012.01387.x

Cited by 54 publications

(72 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S1C). Consistent with OCRL functioning in the cilia of retinal pigmented epithelial cells (4,6,7), the cilia in keratinocytes derived from this patient were defective. Following serum-starvation, these cells exhibited shortened cilia compared with keratinocytes from a healthy individual ( Fig.…”

Section: Resultsmentioning

confidence: 67%

“…The recent discovery of its localization to cilia suggested its potential role in the pathophysiology of glaucoma in the TM of eyes (4,6,7). TRPV4 has been well recognized to be a mechanosensor in kidney epithelial cells, as well as in a number of other fluidregulating cell types (32,37,38,40).…”

Section: Discussionmentioning

confidence: 99%

“…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: 99%

See 2 more Smart Citations

Primary cilia signaling mediates intraocular pressure sensation

Luo

Conwell

Chen

et al. 2014

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

119

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

Section: Resultsmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Primary cilia signaling mediates intraocular pressure sensation

Luo

Conwell

Chen

et al. 2014

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

119

View full text Add to dashboard Cite

show abstract

“…30,31 However, Ocrl1 KD in MDCK cells was reported to cause an increase in ciliary length. 47 Trans Golgi network B Figure 3 Ciliary role of Ocrl1. Notes: (A) Ocrl1 plays a role in trafficking of ciliary destined cargoes via the endocytic and secretory routes involving Rab5-and Rab8-labeled endosomes, respectively.…”

Section: Vesicle Trafficking and Cilium Assemblymentioning

confidence: 99%

“…[41][42][43] The ASH domain also constitutes a binding site for Rabs, with the highest affinity for Rab8a, [44][45][46] leading to an interaction that is critical for Ocrl1 role in ciliogenesis. 30,31,47 The RhoGAP-like domain does not exhibit GTPase-activating protein (GAP) activity but mediates binding to the Rho GTPases Rac1 and Cdc42. 48,49 The ability of Ocrl1 to interact with several Rabs ensures its localization in several cellular compartments.…”

mentioning

confidence: 99%

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

Primary cilia proteins: ciliary and extraciliary sites and functions

Hua

Ferland

2018

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Primary cilia are immotile organelles known for their roles in development and cell signaling. Defects in primary cilia result in a range of disorders named ciliopathies. Because this organelle can be found singularly on almost all cell types, its importance extends to most organ systems. As such, elucidating the importance of the primary cilium has attracted researchers from all biological disciplines. As the primary cilia field expands, caution is warranted in attributing biological defects solely to the function of this organelle, since many of these "ciliary" proteins are found at other sites in cells and likely have non-ciliary functions. Indeed, many, if not all, cilia proteins have locations and functions outside the primary cilium. Extraciliary functions are known to include cell cycle regulation, cytoskeletal regulation, and trafficking. Cilia proteins have been observed in the nucleus, at the Golgi apparatus, and even in immune synapses of T cells (interestingly, a non-ciliated cell). Given the abundance of extraciliary sites and functions, it can be difficult to definitively attribute an observed phenotype solely to defective cilia rather than to some defective extraciliary function or a combination of both. Thus, extraciliary sites and functions of cilia proteins need to be considered, as well as experimentally determined. Through such consideration, we will understand the true role of the primary cilium in disease as compared to other cellular processes' influences in mediating disease (or through a combination of both). Here, we review a compilation of known extraciliary sites and functions of "cilia" proteins as a means to demonstrate the potential non-ciliary roles for these proteins.

show abstract

OCRL1Modulates Cilia Length in Renal Epithelial Cells

Cited by 54 publications

References 70 publications

Primary cilia signaling mediates intraocular pressure sensation

Primary cilia signaling mediates intraocular pressure sensation

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

Primary cilia proteins: ciliary and extraciliary sites and functions

Contact Info

Product

Resources

About