Context-Dependent Regulation of Wnt Signaling through the Primary Cilium

Oh, Edwin C.; Katsanis, Nicholas

doi:10.1681/asn.2012050526

Cited by 65 publications

(66 citation statements)

References 66 publications

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“…4A,B) (Montcouquiol et al 2003;May-Simera and Kelley 2012;Cui et al 2013). Other studies also showed a role for cilia as a switch that can constrain canonical versus noncanonical Wnt signaling (Ross et al 2005;Simons et al 2005;Barrow et al 2007;Gerdes et al 2007;Corbit et al 2008;Huang and Schier 2009;Stottmann et al 2009;Lienkamp et al 2012;Oh and Katsanis 2013). However, the precise mechanism by which cilia regulate Wnt signaling is not well understood.…”

Section: Role Of Wnt Signaling In Cardiac Development and Chdmentioning

confidence: 99%

Cilia and Ciliopathies in Congenital Heart Disease

Klena

Gibbs

2017

Cold Spring Harb Perspect Biol

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A central role for cilia in congenital heart disease (CHD) was recently identified in a largescale mouse mutagenesis screen. Although the screen was phenotype-driven, the majority of genes recovered were cilia-related, suggesting that cilia play a central role in CHD pathogenesis. This partly reflects the role of cilia as a hub for cell signaling pathways regulating cardiovascular development. Consistent with this, many cilia-transduced cell signaling genes were also recovered, and genes regulating vesicular trafficking, a pathway essential for ciliogenesis and cell signaling. Interestingly, among CHD-cilia genes recovered, some regulate left-right patterning, indicating cardiac left-right asymmetry disturbance may play significant roles in CHD pathogenesis. Clinically, CHD patients show a high prevalence of ciliary dysfunction and show enrichment for de novo mutations in cilia-related pathways. Combined with the mouse findings, this would suggest CHD may be a new class of ciliopathy.

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Section: Role Of Wnt Signaling In Cardiac Development and Chdmentioning

confidence: 99%

Cilia and Ciliopathies in Congenital Heart Disease

Klena

Gibbs

2017

Cold Spring Harb Perspect Biol

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“…By these means, primary cilia control cellular processes during development and in the adult organism. 20,[27][28][29][30][31][32][33][34][35][36] In addition, specialized non-motile sensory cilia are present on neurons in the olfactory epithelium of the nasal Table 1. Common types of congenital heart defects Congenital heart defect Abbreviation Characteristics…”

Section: Cilia Ciliopathies and Chd-an Overviewmentioning

confidence: 99%

“…2,189,192,193,196 The link between Wnt signaling and the primary cilium is highly controversial. 32,35,197 However, many Wnt signaling components, such as Fz3, Dvl, and β-catenin, localize to the ciliary/centrosomal axis, and dysregulated Wnt signaling has been reported in cells and tissues with disrupted ciliogenesis or basal body integrity. [198][199][200] Moreover, in the mouse inner ear, establishment of PCP was shown to depend on the formation of functional primary cilia.…”

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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“…This has, in turn, suggested that phenotypes of ciliopathy patients might be attributed to defective paracrine signaling (1), including polydactyly due to defective sonic hedgehog (Shh) signaling (2) and renal cysts attributed to unbalanced Wnt signaling (3). Some data have raised the possibility that a fraction of these defects, especially Wnt, are driven by nonciliary functions of ciliary and basal body proteins (2,4); other findings have indicated that the cilium/basal body Wnt roles are likely specific to discrete spatiotemporal contexts (5)(6)(7)(8)(9).…”

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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Context-Dependent Regulation of Wnt Signaling through the Primary Cilium

Cited by 65 publications

References 66 publications

Cilia and Ciliopathies in Congenital Heart Disease

Cilia and Ciliopathies in Congenital Heart Disease

Cilia and coordination of signaling networks during heart development

Ciliopathy proteins regulate paracrine signaling by modulating proteasomal degradation of mediators

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