Dishevelled stabilization by the ciliopathy protein Rpgrip1l is essential for planar cell polarity

Mahuzier, Alexia; Gaudé, Helori-Mael; Grampa, Valentina; Anselme, Isabelle; Silbermann, Flora; Leroux-Berger, Margot; Delacour, Delphine; Ezan, Jérôme; Montcouquiol, Mireille; Saunier, Sophie; Schneider‐Maunoury, Sylvie; Vesque, Christine

doi:10.1083/jcb.201111009

Cited by 70 publications

(73 citation statements)

References 69 publications

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“…136,142 Septation of the ventricles is also dependent on the gene Fantom (Ftm) 22 that encodes the ciliary base protein Rpgrip1l/Nphp8, which is required for proper ciliogenesis, PCP, and Shh signaling, and when mutated leads to a series of ciliopathies. 22,[52][53][54][160][161][162][163][164][165] In Ftm null mouse embryos, 33% of all analyzed embryos had VSD in the membranous part of the septum, 81.5% had defects in the muscular part, and all analyzed embryos had reduced atrial and ventricular wall thickness. 22 In the ciliated areas of Ftm −/− embryonic hearts at E11.5, the rate of proliferation and Shh signaling was markedly reduced.…”

Section: Cardiac Primary Cilia and Coordination Of Hedgehog Signalingmentioning

confidence: 99%

“…Interestingly, NPHP2-4 and Ftm/Rpgrip1l/NPHP8 all seem to impair canonical Wnt-signaling while promoting non-canonical Wnt responses. 14,165,200,[207][208][209] As an example, NPHP2/inversin and the structurally related diversin in zebrafish are required for convergence extension movement in vertebrates, and depletion of either result in cardiac defects. 190,208 Together, these aspects suggest that inversin and other NPHPs are implicated in heart development by controlling Wnt signaling, but whether this is coordinated by cardiac primary cilia remains speculative at this point.…”

Section: Cardiac Primary Cilia and Other Signaling Pathwaysmentioning

confidence: 99%

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Cilia and coordination of signaling networks during heart development

et al. 2013

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Section: Cardiac Primary Cilia and Coordination Of Hedgehog Signalingmentioning

confidence: 99%

Section: Cardiac Primary Cilia and Other Signaling Pathwaysmentioning

confidence: 99%

Cilia and coordination of signaling networks during heart development

et al. 2013

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“…We and others have reported previously that perturbation of some ciliopathy proteins alters the stability of Wnt signaling mediators such as β-catenin and Dishevelled (5,8,21,29,30). To study the physiological relevance of these findings in vivo, we mated Bbs4 -/-mice with a transgenic proteasome reporter mouse line expressing unstable ubiquitin-tagged GFP (31) to generate Ub G76V -Gfp Bbs4 -/-mice.…”

Section: Accumulation Of Signaling Mediators Upon Depletion Of Ciliopmentioning

confidence: 99%

“…One candidate, the ubiquitin-proteasome system (UPS), is attractive for three reasons. First, the basal body is known to be a proteolytic center (18)(19)(20)(21). Second, we reported previously that disruption of some basal body proteins results in loss of proteasomedependent degradation of β-catenin (5), a phenotype reproduced subsequently (22).…”

Section: Introductionmentioning

confidence: 99%

Ciliopathy proteins regulate paracrine signaling by modulating proteasomal degradation of mediators

et al. 2014

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Cilia are critical mediators of paracrine signaling; however, it is unknown whether proteins that contribute to ciliopathies converge on multiple paracrine pathways through a common mechanism. Here, we show that loss of cilopathy-associated proteins Bardet-Biedl syndrome 4 (BBS4) or oral-facial-digital syndrome 1 (OFD1) results in the accumulation of signaling mediators normally targeted for proteasomal degradation. In WT cells, several BBS proteins and OFD1 interacted with proteasomal subunits, and loss of either BBS4 or OFD1 led to depletion of multiple subunits from the centrosomal proteasome. Furthermore, overexpression of proteasomal regulatory components or treatment with proteasomal activators sulforaphane (SFN) and mevalonolactone (MVA) ameliorated signaling defects in cells lacking BBS1, BBS4, and OFD1, in morphant zebrafish embryos, and in induced neurons from Ofd1-deficient mice. Finally, we tested the hypothesis that other proteasome-dependent pathways not known to be associated with ciliopathies are defective in the absence of ciliopathy proteins. We found that loss of BBS1, BBS4, or OFD1 led to decreased NF-κB activity and concomitant IκBβ accumulation and that these defects were ameliorated with SFN treatment. Taken together, our data indicate that basal body proteasomal regulation governs paracrine signaling pathways and suggest that augmenting proteasomal function might benefit ciliopathy patients.

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“…19 Stable human podocyte cell lines were obtained by transduction of the shIFT139 lentiviral particles, followed by puromycin selection (2 mg/ml). For rescue experiments, IFT139 depleted cells were transduced with the wild-type or mutant IFT139 constructs.…”

Section: Plasmids Cell Culture and Establishment Of Lentiviral Cellmentioning

confidence: 99%

A Homozygous Missense Mutation in the Ciliary Gene TTC21B Causes Familial FSGS

Cong

Bizet

Boyer

et al. 2014

Journal of the American Society of Nephrology

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Several genes, mainly involved in podocyte cytoskeleton regulation, have been implicated in familial forms of primary FSGS. We identified a homozygous missense mutation (p.P209L) in the TTC21B gene in seven families with FSGS. Mutations in this ciliary gene were previously reported to cause nephronophthisis, a chronic tubulointerstitial nephropathy. Notably, tubular basement membrane thickening reminiscent of that observed in nephronophthisis was present in patients with FSGS and the p.P209L mutation. We demonstrated that the TTC21B gene product IFT139, an intraflagellar transport-A component, mainly localizes at the base of the primary cilium in developing podocytes from human fetal tissue and in undifferentiated cultured podocytes. In contrast, in nonciliated adult podocytes and differentiated cultured cells, IFT139 relocalized along the extended microtubule network. We further showed that knockdown of IFT139 in podocytes leads to primary cilia defects, abnormal cell migration, and cytoskeleton alterations, which can be partially rescued by p.P209L overexpression, indicating its hypomorphic effect. Our results demonstrate the involvement of a ciliary gene in a glomerular disorder and point to a critical function of IFT139 in podocytes. Altogether, these data suggest that this homozygous TTC21B p.P209L mutation leads to a novel hereditary kidney disorder with both glomerular and tubulointerstitial damages.

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Dishevelled stabilization by the ciliopathy protein Rpgrip1l is essential for planar cell polarity

Abstract: Rpgrip1l is required for planar localization of the basal body and acts within a ciliopathy protein complex by stabilizing dishevelled.

Cited by 70 publications

References 69 publications

Cilia and coordination of signaling networks during heart development

Cilia and coordination of signaling networks during heart development

Ciliopathy proteins regulate paracrine signaling by modulating proteasomal degradation of mediators

A Homozygous Missense Mutation in the Ciliary Gene TTC21B Causes Familial FSGS

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