Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells

Nauli, Surya M.; Alenghat, Francis J.; Luo, Ying; Williams, Eric O.; Vassilev, Peter; Li, Yong; Elia, Andrew E. H.; Lu, Weining; Brown, Edward M.; Quinn, Stephen; Ingber, Donald E.; Zhou, Jing

doi:10.1038/ng1076

Cited by 1,828 publications

(2,017 citation statements)

References 44 publications

Supporting

Mentioning

1,894

Contrasting

Unclassified

Order By: Relevance

“…Here we show that recessive mutations in INVS cause NPHP2 with and without situs inversus and that inversin interacts with nephrocystin. We show that both proteins localize to primary cilia of renal tubular cells, the same subcellular compartment that has been recently identified as central to the pathogenesis of PKD 20,21 . …”

supporting

confidence: 56%

“…These proteins have a role in ciliogenesis, cilia maintenance and intraflagellar transport 20 and, most importantly, mediate mechanosensation of cilia and cell cycle control 28,21 . These proteins include polaris, polycystin-1 and polycystin-2 (with their respective homologs in C. elegans osm-5 (refs.…”

Section: Discussionmentioning

confidence: 99%

“…Very recently, polycystin-1 and polycystin-2 have been shown to function in a shared pathway of mechanotransduction exerted by the primary cilia of renal epithelia. Inability of these cells to sense mechanical cues may be causative for the defect in tissue morphogenesis that leads to the PKD phenotype 21 . Whereas in PKD one network of pathogenic factors is clustered around proteins of primary cilia, another functional cluster involves mechanisms of cell-cell signaling 34 .…”

Section: Discussionmentioning

confidence: 99%

“…Recent evidence has suggested an association between structural or functional defects in the primary apical cilium of kidney epithelia and PKD 20,21 . We therefore investigated whether nephrocystin is a component of primary cilia as suggested by proteomics data 24 .…”

Section: Nephrocystin and Inversin Colocalize With β-Tubulin To Ciliamentioning

confidence: 99%

See 3 more Smart Citations

Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination

et al. 2003

View full text Add to dashboard Cite

Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, leads to chronic renal failure in children. The genes mutated in NPHP1 and NPHP4 have been identified, and a gene locus associated with infantile nephronophthisis (NPHP2) was mapped. The kidney phenotype of NPHP2 combines clinical features of NPHP and polycystic kidney disease (PKD). Here, we identify inversin (INVS) as the gene mutated in NPHP2 with and without situs inversus. We show Correspondence should be addressed to F.H. (fhilde@umich.edu). 12 These authors contributed equally to this work 13 These authors contributed equally to this work GenBank accession numbers. INVS cDNA, NM_014425; Invs cDNA, NM_010569; invs cDNA, AF465261; INVS in chromosome 9 genome contig, NT_008470.URLs. Additional information is available at http://danio.mgh.harvard.edu/blast/blast.html. Note: Supplementary information is available on the Nature Genetics website. Competing Interests Statement:The authors declare that they have no competing financial interests. NIH Public AccessAuthor Manuscript Nat Genet. Author manuscript; available in PMC 2013 August 02. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript molecular interaction of inversin with nephrocystin, the product of the gene mutated in NPHP1 and interaction of nephrocystin with β-tubulin, a main component of primary cilia. We show that nephrocystin, inversin and β-tubulin colocalize to primary cilia of renal tubular cells. Furthermore, we produce a PKD-like renal cystic phenotype and randomization of heart looping by knockdown of invs expression in zebrafish. The interaction and colocalization in cilia of inversin, nephrocystin and β-tubulin connect pathogenetic aspects of NPHP to PKD, to primary cilia function and to leftright axis determination.NPHP, an autosomal recessive cystic kidney disease, is the most frequent genetic cause for end-stage renal failure in children and young adults [1][2][3] . Causative mutations in two genes (NPHP1 and NPHP4) have been identified by positional cloning [4][5][6][7] . There is considerable interest in identifying genes associated with NPHP because its most prominent feature is development of renal interstitial fibrosis 8 , which in chronic renal disease of all origin represents the pathogenic event correlated most strongly to loss of renal function 9 . As little was known about the pathogenesis of NPHP, positional cloning was used to identify a new gene, NPHP1, mutations in which cause NPHP1 (OMIM 256100; refs. 4,5). It encodes a novel docking protein, nephrocystin [10][11][12][13] , that interacts with components of cell-cell and cell-matrix signaling, such as focal adhesion kinase 2, tensin, p130Cas and filamin, and with nephrocystin-4 or nephroretinin, the product of NPHP4, mutations in which cause NPHP4 (OMIM 606966; refs. 6,7). Identification of the genes NPHP1 and NPHP4, which are conserved in evolution including in the nematode Caenorhabditis elegans, offered new insights into mechanisms of cell-cell and cell-matrix signaling...

show abstract

supporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Nephrocystin and Inversin Colocalize With β-Tubulin To Ciliamentioning

confidence: 99%

See 2 more Smart Citations

Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination

et al. 2003

View full text Add to dashboard Cite

show abstract

“…These include the basolateral plasma membrane of epithelial cells [64]; the endoplasmic reticulum This is the Pre-Published Version (ER) where it may operate as a Ca 2+ -release channel [65], and the primary cilia where it is thought to participate in mechanosensation [66]. The function of TRPP2 in primary cilia has been linked to the formation of kidney cysts in vertebrates.…”

Section: Trp Channels Are Involved In the Generation Of The Ca 2+ Sigmentioning

confidence: 99%

Ca2+ coding and decoding strategies for the specification of neural and renal precursor cells during development

et al. 2016

View full text Add to dashboard Cite

The Centrosome in Evolution

Azimzadeh

Bornens

2004

Centrosomes in Development and Disease

View full text Add to dashboard Cite

Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells

Cited by 1,828 publications

References 44 publications

Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination

Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination

Ca2+ coding and decoding strategies for the specification of neural and renal precursor cells during development

The Centrosome in Evolution

Contact Info

Product

Resources

About