Functional characterization of the C. elegans nephrocystins NPHP-1 and NPHP-4 and their role in cilia and male sensory behaviors

Jauregui, Andrew R.; Barr, Maureen M.

doi:10.1016/j.yexcr.2005.01.008

Cited by 54 publications

(50 citation statements)

References 48 publications

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“…However, a striking difference between rd16 and Bbs-null mice is that olfactory cilia remain intact with hypomorphic mutations in CEP290. This is consistent with earlier studies in C. elegans, in which mutations in nephrocystins specifically affected chemosensation and sensory behavior without altering ciliary assembly or maintenance (18,19,35). Furthermore, the odorant receptors ACIII and CNGA2 remained localized to OSNs cilia, suggesting that in-frame deletion of CEP290 selectively alters protein transport into the cilia.…”

Section: Discussionsupporting

confidence: 91%

Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons

McEwen¹,

Koenekoop

Khanna

et al. 2007

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

146

156

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Cilia regulate diverse functions such as motility, fluid balance, and sensory perception. The cilia of olfactory sensory neurons (OSNs) compartmentalize the signaling proteins necessary for odor detection; however, little is known regarding the mechanisms of protein sorting/entry into olfactory cilia. Nephrocystins are a family of ciliary proteins likely involved in cargo sorting during transport from the basal body to the ciliary axoneme. In humans, loss-offunction of the cilia-centrosomal protein CEP290/NPHP6 is associated with Joubert and Meckel syndromes, whereas hypomorphic mutations result in Leber congenital amaurosis (LCA), a form of early-onset retinal dystrophy. Here, we report that CEP290 -LCA patients exhibit severely abnormal olfactory function. In a mouse model with hypomorphic mutations in CEP290 [retinal dystrophy-16 mice (rd16)], electro-olfactogram recordings revealed an anosmic phenotype analogous to that of CEP290 -LCA patients. Despite the loss of olfactory function, cilia of OSNs remained intact in the rd16 mice. As in wild type, CEP290 localized to dendritic knobs of rd16 OSNs, where it was in complex with ciliary transport proteins and the olfactory G proteins G olf and G␥13. Interestingly, we observed defective ciliary localization of G olf and G␥13 but not of G protein-coupled odorant receptors or other components of the odorant signaling pathway in the rd16 OSNs. Our data implicate distinct mechanisms for ciliary transport of olfactory signaling proteins, with CEP290 being a key mediator involved in G protein trafficking. The assessment of olfactory function can, therefore, serve as a useful diagnostic tool for genetic screening of certain syndromic ciliary diseases.nephrocystin ͉ olfaction

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Section: Discussionsupporting

confidence: 91%

Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons

McEwen¹,

Koenekoop

Khanna

et al. 2007

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

146

156

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“…Both NPHP-2S and NPHP-2L localized to the middle segment at all stages of development, from larval stage L1 to young adult (data not shown). The middle segment localization of NPHP-2S and NPHP-2L differs markedly from the TZ localization of most other cystoproteins, including NPHP-1, NPHP-4, MKS-1 and MKS-6 (Bialas et al, 2009;Jauregui and Barr, 2005;Williams et al, 2008;Williams et al, 2011;Winkelbauer et al, 2005). To confirm middle segment localization, the length of the NPHP-2S and NPHP-2L localizations was measured (2.560.59 mm) and was found to be similar to the length of the MS as measured by electron microscopy (2-3 mm) (David Hall, personal communication).…”

Section: Y32g9a6 Is the C Elegans Ortholog Of Inversinmentioning

confidence: 75%

“…BBS-1, BBS-7, BBS-8), or localize to the TZ-basal body complex (e.g. NPHP-1, NPHP-4, MKS-1, MKS-3, MKS-6) (Bialas et al, 2009;Blacque et al, 2004;Garcia-Gonzalo et al, 2011;Jauregui and Barr, 2005;Qin et al, 2001;Williams et al, 2008;Winkelbauer et al, 2005). This TZ complex is necessary for early ciliogenesis and the TZ is a region associated with traffic into and out of the cilium (Williams et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Mammalian NPHP1 (also known as JBTS4) and NPHP4 physically interact to form a complex (Mollet et al, 2002). In C. elegans, nphp-1 and nphp-4 single and double mutants have superficially normal cilia, though transmission electron microscopy reveals subtle ultrastructural defects (Jauregui and Barr, 2005;Jauregui et al, 2008;Winkelbauer et al, 2005). Neither is required for localization of the ciliary receptors OSM-9 and PKD-2; however, mutations in nphp-4 indirectly affect the velocity of several IFT subcomponents (Jauregui et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Ciliogenesis inCaenorhabditis elegansrequires genetic interactions between ciliary middle segment localized NPHP-2 (inversin) and transition zone-associated proteins

Warburton-Pitt

Jauregui

et al. 2012

Journal of Cell Science

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SummaryThe cystic kidney diseases nephronophthisis (NPHP), Meckel-Gruber syndrome (MKS) and Joubert syndrome (JBTS) share an underlying etiology of dysfunctional cilia. Patients diagnosed with NPHP type II have mutations in the gene INVS (also known as NPHP2), which encodes inversin, a cilia localizing protein. Here, we show that the C. elegans inversin ortholog, NPHP-2, localizes to the middle segment of sensory cilia and that nphp-2 is partially redundant with nphp-1 and nphp-4 (orthologs of human NPHP1 and NPHP4, respectively) for cilia placement within the head and tail sensilla. nphp-2 also genetically interacts with MKS ciliopathy gene orthologs, including mks-1, mks-3, mks-6, mksr-1 and mksr-2, in a sensilla-dependent manner to control cilia formation and placement. However, nphp-2 is not required for correct localization of the NPHP-and MKS-encoded ciliary transition zone proteins or for intraflagellar transport (IFT). We conclude that INVS/NPHP2 is conserved in C. elegans and that nphp-2 plays an important role in C. elegans cilia by acting as a modifier of the NPHP and MKS pathways to control cilia formation and development.

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“…It is interesting that mutations in these genes in C. elegans did not disrupt cilia formation but did cause behavioral defects that are typical of those that are seen in mutants that lack cilia-mediated signaling activity (67,69). As for the mammalian proteins, the C. elegans NPHP proteins function as part of a complex as evidence by the fact that disruption of NPHP-4 causes the delocalization of NPHP-1 from the base of the cilium (69).…”

Section: Cilia and Non-pkd Forms Of Cystic Kidney Diseasementioning

confidence: 99%

Role of Primary Cilia in the Pathogenesis of Polycystic Kidney Disease

Yoder¹

2007

Journal of the American Society of Nephrology

261

223

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Cysts in the kidney are among the most common inherited human pathologies, and recent research has uncovered that a defect in cilia-mediated signaling activity is a key factor that leads to cyst formation. The cilium is a microtubule-based organelle that is found on most cells in the mammalian body. Multiple proteins whose functions are disrupted in cystic diseases have now been localized to the cilium or at the basal body at the base of the cilium. Current data indicate that the cilium can function as a mechanosensor to detect fluid flow through the lumen of renal tubules. Flow-mediated deflection of the cilia axoneme induces an increase in intracellular calcium and alters gene expression. Alternatively, a recent finding has revealed that the intraflagellar transport 88/polaris protein, which is required for cilia assembly, has an additional role in regulating cell-cycle progression independent of its function in ciliogenesis. Further research directed at understanding the relationship between the cilium, cell-cycle, and cilia-mediated mechanosensation and signaling activity will hopefully provide important insights into the mechanisms of renal cyst pathogenesis and lead to better approaches for therapeutic intervention.

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Functional characterization of the C. elegans nephrocystins NPHP-1 and NPHP-4 and their role in cilia and male sensory behaviors

Cited by 54 publications

References 48 publications

Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons

Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons

Ciliogenesis inCaenorhabditis elegansrequires genetic interactions between ciliary middle segment localized NPHP-2 (inversin) and transition zone-associated proteins

Role of Primary Cilia in the Pathogenesis of Polycystic Kidney Disease

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