Nephronophthisis

Hildebrandt, Friedhelm; Attanasio, Massimo; Otto, Edgar A.

doi:10.1681/asn.2008050456

Cited by 330 publications

(373 citation statements)

References 140 publications

(212 reference statements)

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“…Protruding from the cell into its environment, the cilium is involved in multiple signaling pathways, including the Sonic hedgehog (Shh) pathway, the Wnt pathways, and the target of rapamycin (TOR) pathway. [1][2][3][4][5] Not surprisingly, defects in the cilium have been linked to a growing list of human diseases, coined "ciliopathies," ranging from laterality defects, retinal degeneration, polycystic kidney disease (PKD), and other hepatorenal fibrocystic disorders to obesity and diabetes (for a review, see reference 6).…”

mentioning

confidence: 99%

Intraflagellar Transport Proteins Are Essential for Cilia Formation and for Planar Cell Polarity

Cao

Park

Sun

2010

Journal of the American Society of Nephrology

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The highly conserved intraflagellar transport (IFT) proteins are essential for cilia formation in multiple organisms, but surprisingly, cilia form in multiple zebrafish ift mutants. Here, we detected maternal deposition of ift gene products in zebrafish and found that ciliary assembly occurs only during early developmental stages, supporting the idea that maternal contribution of ift gene products masks the function of IFT proteins during initial development. In addition, the basal bodies in multiciliated cells of the pronephric duct in ift mutants were disorganized, with a pattern suggestive of defective planar cell polarity (PCP). Depletion of pk1, a core PCP component, similarly led to kidney cyst formation and basal body disorganization. Furthermore, we found that multiple ift genes genetically interact with pk1. Taken together, these data suggest that IFT proteins play a conserved role in cilia formation and planar cell polarity in zebrafish.

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mentioning

confidence: 99%

Intraflagellar Transport Proteins Are Essential for Cilia Formation and for Planar Cell Polarity

Cao

Park

Sun

2010

Journal of the American Society of Nephrology

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“…Asymmetric cell division can lead to various human diseases (Morrison & Kimble, 2006; Hildebrandt et al , 2009, 2011). Therefore, we next examined whether phosphorylation of INVS affects spindle alignment during cell division.…”

Section: Resultsmentioning

confidence: 99%

“…When tubules elongate during renal development, tubular cells undergo massive proliferation (Simons & Walz, 2006). Further, Hildebrandt reported that defects in cystoproteins lead to disruption of PCP and formation of renal cysts due to malorientation of the centrosome or the mitotic spindle complex (Hildebrandt et al , 2009, 2011). Consistently, Happe reported that the renal cyst is characterized by a progressive development of fluid‐filled cyst derived from renal tubular epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation‐dependent Akt–Inversin interaction at the basal body of primary cilia

et al. 2016

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A primary cilium is a microtubule‐based sensory organelle that plays an important role in human development and disease. However, regulation of Akt in cilia and its role in ciliary development has not been demonstrated. Using yeast two‐hybrid screening, we demonstrate that Inversin (INVS) interacts with Akt. Mutation in the INVS gene causes nephronophthisis type II (NPHP2), an autosomal recessive chronic tubulointerstitial nephropathy. Co‐immunoprecipitation assays show that Akt interacts with INVS via the C‐terminus. In vitro kinase assays demonstrate that Akt phosphorylates INVS at amino acids 864–866 that are required not only for Akt interaction, but also for INVS dimerization. Co‐localization of INVS and phosphorylated form of Akt at the basal body is augmented by PDGF‐AA. Akt‐null MEF cells as well as siRNA‐mediated inhibition of Akt attenuated ciliary growth, which was reversed by Akt reintroduction. Mutant phosphodead‐ or NPHP2‐related truncated INVS, which lack Akt phosphorylation sites, suppress cell growth and exhibit distorted lumen formation and misalignment of spindle axis during cell division. Further studies will be required for elucidating functional interactions of Akt–INVS at the primary cilia for identifying the molecular mechanisms underlying NPHP2.

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“…Successful renal transplantations have been performed in patients with juvenile nephronophthisis, without the recurrence of the disease in the transplanted organ. An important future challenge will be the development of therapies that capitalizes on what we have learnt about the biology of NPHP and other cystic disease of the kidney [23]. Currently, next generation sequencing (NGS) that is also known as massively parallel sequencing and clinical perspectives is mostly used for research purposes in order to identify novel disease genes and to gain more insights into genotype-phenotype correlations in a time and cost effective effort.…”

Section: Discussionmentioning

confidence: 99%