Cilia, Wnt signaling, and the cytoskeleton

May-Simera, Helen; Kelley, Matthew W.

doi:10.1186/2046-2530-1-7

Cited by 133 publications

(124 citation statements)

References 149 publications

(174 reference statements)

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“…Primary cilia also play a role in the transduction of canonical and noncanonical Wnt signaling (Clevers 2006;MacDonald et al 2009;Wallingford and Mitchell 2011;May-Simera and Kelley 2012) pathways that are also essential for normal heart development. One early evidence linking cilia with b-catenin-dependent canonical Wnt signaling was the observation that knockdown of basal body components bbs1, bbs4, and bss6 resulted in several-fold increase in Wnt activity in zebrafish (Gerdes et al 2007).…”

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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“…35,36 The non-canonical Wnt pathway is controlled by a membrane protein called Van Gogh-like 2 (Vangl2) and regulates cytoskeletal changes, cell adhesion, migration and polarity. 37 Vangl2 functions in asymmetric positioning of MC and in centrosome positioning, which is important for cytoskeletal rearrangement. Mutations of different ciliary proteins, such as Kif3a, Ift88, Ofd1 (the protein mutated in oral-facial-digital syndrome type 1), polycystin 1 (PC1) and polycystin 2 (PC2), result in dysregulation of planar cell polarity (PCP) and are associated with hyper-or de-activation of the Wnt pathway depending of the tissue, timing, and localization of these proteins.…”

Section: Cilium: Structure and Signalingmentioning

confidence: 99%

“…Inversin serves as a molecular switch between canonical and noncanonical Wnt pathways by regulating Disheveled protein degradation at the basal body by the adenomatosis polyposis complex (APC). 37 The canonical Wnt pathway is regulated by β-catenin and controls proliferation, apoptosis and cell fate determination via activation of target genes. The connection between the canonical Wnt pathway and PC seems to be linear.…”

Section: Cilium: Structure and Signalingmentioning

confidence: 99%

“…These findings shed light on the contribution of the interaction of Wnt pathway with the PC in the regulation of cytoskeletal architecture. 37 Calcium signaling. The Ca 2+ -specific cation channel PC2, which forms an ion channel complex with the G-protein coupled receptor PC1 localized in the axoneme, regulates calcium signaling.…”

Section: Cilium: Structure and Signalingmentioning

confidence: 99%

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Autophagy and regulation of cilia function and assembly

et al. 2014

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Motile and primary cilia (PC) are microtubule-based structures located at the cell surface of many cell types. Cilia govern cellular functions ranging from motility to integration of mechanical and chemical signaling from the environment. Recent studies highlight the interplay between cilia and autophagy, a conserved cellular process responsible for intracellular degradation. Signaling from the PC recruits the autophagic machinery to trigger autophagosome formation. Conversely, autophagy regulates ciliogenesis by controlling the levels of ciliary proteins. The cross talk between autophagy and ciliated structures is a novel aspect of cell biology with major implications in development, physiology and human pathologies related to defects in cilium function. Cell Death and Differentiation (2015) 22, 389-397; doi:10.1038/cdd.2014.171; published online 31 October 2014 FactsAutophagy is a degradative and recycling mechanism that allows cells to adapt to stress situations including nutrient deprivation. Primary cilia (PC) and motile cilia (MC) are sensory structures at the cell surface. PC sense nutrient, growth factor and calcium changes in the extracellular environment and also respond to mechanical stress. MC are beating structures that contribute to innate defense in the lung, for example. The PC is a site for the recruitment of autophagy-related (ATG) proteins that mediate autophagosome formation in response to cilium-dependent signaling. In turn, autophagy regulates the biogenesis of cilia by degrading certain proteins involved in cilia formation. Modulation of autophagy represents a new therapeutic opportunity in diseases related to defective cilia function. Open QuestionsHow are ATG proteins transported to the PC? How do ATG proteins recruited to the PC contribute to the biogenesis of phagophores and autophagosomes? Ciliary proteins are degraded by autophagy. How selective is this degradative pathway? Do some of these proteins contain motifs that result in selective engulfment by autophagosomes?What are the determinants that switch the degradation of ciliary proteins between basal and induced autophagy? Is there any specific function for cilium-dependent autophagy in ciliated cells? Do signals that trigger cilium-dependent autophagy depend on the stimuli (chemical, mechanical) or do all stimuli converge to a single signaling pathway upstream of the autophagy machinery? Can modulation of autophagy contribute to the restoration of cilium functions?Receptors, transporters and specialized plasma membrane structures such as cilia constitute the interfaces between the extracellular and intracellular milieu and allow the cells to trigger specific responses to adapt to changes imposed by the environment. Among these adaptive responses, macroautophagy (hereafter referred to as 'autophagy') is a catabolic process conserved in eukaryotic cells by which the cell recycles its own constituents. 1 Autophagy is involved in the adaptation to starvation, cell differentiation and development, the degradation of aberrant structure...

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“…Reduced primary cilia expression has been observed in human cancers, such as pancreatic cancer, renal cell carcinoma, breast cancer, and melanoma. Studies suggest that primary cilia is dysfunctional in human prostate cancer, and increasesWnt signaling occuredin a subset of cancers (14).…”

Section: Introductionmentioning

confidence: 99%

Wnt Signaling Inhibits the Growth of Primary Cilia and Activates CyclinD1, Snail and VEGFA Expression in Breast Cancer Cell Line MDA-MB-231

Deng¹

2015

AJLS

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Abstract:Although Wnt/β-catenin signaling has been shown to be essential in the process of cancer formation, it is unclear how Wnt3a signaling pathway regulates abnormal proliferation and differentiation of breast cancer cells. Here, we found overexpression of Wnt3a stimulated the expression of the Wntsignaling's downstream genes such as LRP6, Naked, Axin1, DVL-2, β-catenin, and TCF-1 in breast cancer cell line MDA-MB-231.Primarycilia is deemed as sensory cell antennae thatcoordinates a large number of cellular signaling pathways, sometimes coupling cell division and differentiation. Primary cilia were found on the surface of this cell line. Overexpression of Wnt3a decreased the formation of primary cilia. Inhibition of Wnt3a with Calphostin C facilitated growth of primary cilia. Wnt3a activated cell proliferation gene of CyclinD1. In contrary, Calphostin C decreased the promotional effect on proliferation of MDA-MB-231. The Snail family of transcription factor has previously been implicated in the differentiation of epithelial cells into mesenchymal cells (epithelial-mesenchymal transitions) during embryonic development. Wnt3a promoted MDA-MB-231 induced expression of Snail, whose effect was inhibited by Calphostin-C. VEGFA activity was originally referred to as vascular permeability factor and had been shown to stimulate endothelial cell mitogenesis and cell migration and increased microvascular permeability. Wnt3a facilitated MDA-MB-231 induced expression of VEGFA, as well as Calphostin-C suppressed its effect. Taken together, these results suggested thatWnt3a signaling played an important role in regulating the formation of breast cancer.

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Cilia, Wnt signaling, and the cytoskeleton

Cited by 133 publications

References 149 publications

Cilia and Ciliopathies in Congenital Heart Disease

Cilia and Ciliopathies in Congenital Heart Disease

Autophagy and regulation of cilia function and assembly

Wnt Signaling Inhibits the Growth of Primary Cilia and Activates CyclinD1, Snail and VEGFA Expression in Breast Cancer Cell Line MDA-MB-231

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