The ciliary Evc/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia.

Instituto de Investigaciones Biomédicas de Madrid (CSIC-UAM), Arturo Duperier 4, Madrid 28029, Spain.
Human Molecular Genetics (Impact Factor: 6.68). 10/2012; DOI: 10.1093/hmg/dds409
Source: PubMed

ABSTRACT Hedgehog (Hh) signaling is involved in patterning and morphogenesis of most organs in the developing mammalian embryo. Despite many advances in understanding core components of the pathway, little is known about how the activity of the Hh pathway is adjusted in organ- and tissue-specific developmental processes. Mutations in EVC or EVC2 disrupt Hh signaling in tooth and bone development. Using mouse models, we show here that Evc and Evc2 are mutually required for localizing to primary cilia and also for maintaining their normal protein levels. Consistent with Evc and Evc2 functioning as a complex, the skeletal phenotypes in either single or double homozygous mutant mice are virtually indistinguishable. Smo translocation to the cilium was normal in Evc2-deficient chondrocytes following Hh activation with the Smo-agonist SAG. However, Gli3 recruitment to cilia tips was reduced and Sufu/Gli3 dissociation was impaired. Interestingly, we found Smo to co-precipitate with Evc/Evc2, indicating that in some cells Hh signaling requires direct interaction of Smo with the Evc/Evc2 complex. Expression of a dominantly acting Evc2 mutation previously identified in Weyer's acrodental dysostosis (Evc2Δ43) caused mislocalization of Evc/Evc2Δ43 within the cilium and also reproduced the Gli3-related molecular defects observed in Evc2(-/-) chondrocytes. Moreover, Evc silencing in Sufu(-/-) cells attenuated the output of the Hh pathway, suggesting that Evc/Evc2 also promote Hh signaling in the absence of Sufu. Together our data reveal that the Hh pathway involves Evc/Evc2-dependent modulations that are necessary for normal endochondral bone formation.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Primary cilia are microtubule-based organelles that project from the cell surface to enable transduction of various developmental signaling pathways. The process of intraflagellar transport (IFT) is crucial for the building and maintenance of primary cilia. Ciliary dysfunction has been found in a range of disorders called ciliopathies, some of which display severe skeletal dysplasias. In recent years, interest has grown in uncovering the function of primary cilia/IFT proteins in bone development, mechanotransduction, and cellular regulation. We summarize recent advances in understanding the function of cilia and IFT proteins in the regulation of cell differentiation in osteoblasts, osteocytes, chondrocytes, and mesenchymal stem cells (MSCs). We also discuss the mechanosensory function of cilia and IFT proteins in bone cells, cilia orientation, and other functions of cilia in chondrocytes.
    Annals of the New York Academy of Sciences 06/2014; · 4.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The presence and role of primary, or non-motile, cilia on chondrocytes has confused cartilage researchers for decades. Initial explanations attributed a vestigial nature to chondrocyte cilia. Evidence is now emerging that supports the role of the chondrocyte primary cilium as a sensory organelle, in particular, in mechanotransduction and as a compartment for signaling pathways. Early electron microscopy images depicted bent cilia aligned with the extracellular matrix in a manner that suggested a response to mechanical forces. Molecules known to be mechanotransducers in other cell types, including integrins and proteoglycans, are present on chondrocyte cilia. Further, chondrocytes which lack cilia fail to respond to mechanical forces in the same manner that chondrocytes with intact cilia respond. From a clinical perspective, chondrocytes from osteoarthritic cartilage have cilia with different characteristics than cilia found on chondrocytes from healthy cartilage. This review examines the evidence supporting the function of chondrocyte cilia and briefly speculates on the involvement of intraflagellar transport in the signaling pathway of mechanotransduction through the cilium. Emerging evidence suggests cilia may be a promising target for preventing and treating osteoarthritis.
    Osteoarthritis and Cartilage 05/2014; · 4.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Activation of hepatic stellate cells (HSCs) is a pivotal cellular event in liver fibrosis. Therefore, improving our understanding of the molecular pathways that are involved in these processes is essential to generate new therapies for liver fibrosis. Greater knowledge of the role of the hedgehog signaling pathway in liver fibrosis could improve understanding of the liver fibrosis pathogenesis. Areas covered: The aim of this review is to describe the present knowledge about the hedgehog signaling pathway, which significantly participates in liver fibrosis and HSC activation, and look ahead on new perspectives of hedgehog signaling pathway research. Moreover, we will discuss the different interactions with hedgehog signaling pathway-regulated liver fibrosis. Expert opinion: The hedgehog pathway modulates several important aspects of function, including cell proliferation, activation and differentiation. Targeting the hedgehog pathway can be a promising direction in liver fibrosis treatment. We discuss new perspectives of hedgehog signaling pathway activation in liver fibrosis and HSC fate, including DNA methylation, methyl CpG binding protein 2, microRNA, irradiation and metabolism that influence hedgehog signaling pathway transduction. These findings identify the hedgehog pathway as a potentially important for biomarker development and therapeutic targets in liver fibrosis. Future studies are needed in order to find safer and more effective hedgehog-based drugs.
    Expert Opinion on Therapeutic Targets 06/2014; · 4.90 Impact Factor


Available from
May 28, 2014