Mouse Kif7/Costal2 is a cilia-associated protein that regulates Sonic hedgehog signaling

ArticleinProceedings of the National Academy of Sciences 106(32):13377-82 · August 2009with22 Reads
DOI: 10.1073/pnas.0906944106 · Source: PubMed
Abstract
Mammalian Sonic hedgehog (Shh) signaling is essential for embryonic development and stem cell maintenance and has critical roles in tumorigenesis. Although core components of the Shh pathway are conserved in evolution, important aspects of mammalian Shh signaling are not shared with the Drosophila pathway. Perhaps the most dramatic difference between the Drosophila and mammalian pathways is that Shh signaling in the mouse requires a microtubule-based organelle, the primary cilium. Proteins that are required for the response to Shh are enriched in the cilium, but it is not clear why the cilium provides an appropriate venue for signal transduction. Here, we demonstrate that Kif7, a mammalian homologue of Drosophila Costal2 (Cos2), is a cilia-associated protein that regulates signaling from the membrane protein Smoothened (Smo) to Gli transcription factors. By using a Kif7 mutant allele identified in a reporter-based genetic screen, we show that, similar to Drosophila and zebrafish Cos2, mouse Kif7 acts downstream of Smo and upstream of Gli2 and has both negative and positive roles in Shh signal transduction. Mouse Kif7 activity depends on the presence of cilia and Kif7-eGFP localizes to base of the primary cilium in the absence of Shh. Activation of the Shh pathway promotes trafficking of Kif7-eGFP from the base to the tip of the cilium, and localization to the tip of the cilium is disrupted in a motor domain mutant. We conclude that Kif7 is a core regulator of Shh signaling that may also act as a ciliary motor.
    • "Loss of Tbx3 decreases Kif7-Sufu interactions, resulting in excess Gli3 proteolysis and decreased levels of both Gli3FL and Gli3R. The resulting preaxial polydactyly phenocopies limb defects seen in Gli3 null heterozygotes and in mutants with abnormal structure or function of the primary cilia (Cheung et al., 2009; Endoh-Yamagami et al., 2009; Goetz and Anderson, 2010; Haycraft et al., 2005; Liem et al., 2009; Liu et al., 2005; Ocbina et al., 2011; Putoux et al., 2011). Our findings reveal a novel mechanism where Tbx3 in the anterior mesenchyme is required for proper function of the Kif7/Sufu complex that regulates Gli3 stability and processing. "
    Full-text · Article · Apr 2016 · Stem cell International
    • "Interestingly, the vertebrate Cos2 homolog Kif7 organizes the distal compartment of vertebrate primary cilia (He et al., 2014). Similar to our results, Kif7 does so without affecting the IFT system , and its localization to the cilia is dependent on Hh signaling (Endoh-Yamagami et al., 2009; He et al., 2014; Liem et al., 2009). However, the Kif7 kinesin motor function has been questioned (He et al., 2014). "
    [Show abstract] [Hide abstract] ABSTRACT: Hedgehog (Hh) signaling is a key regulatory pathway during development and also has a functional role in mature neurons. Here, we show that Hh signaling regulates the odor response in adult Drosophila olfactory sensory neurons (OSNs). We demonstrate that this is achieved by regulating odorant receptor (OR) transport to and within the primary cilium in OSN neurons. Regulation relies on ciliary localization of the Hh signal transducer Smoothened (Smo). We further demonstrate that the Hh- and Smo-dependent regulation of the kinesin-like protein Cos2 acts in parallel to the intraflagellar transport system (IFT) to localize ORs within the cilium compartment. These findings expand our knowledge of Hh signaling to encompass chemosensory modulation and receptor trafficking.
    Full-text · Article · Jan 2016
    • "Recent studies reveal specific roles of discrete ciliary regulators, components, and structures in controlling the movement and signaling of Hh components. Active Hh signalling is associated with increased levels of Hh components along the primary cilium or in a ciliary subdomain [23, 26]. On ligand binding to its membrane receptor Ptch1, a dramatic reduction in Ptch1 expression ensues concomitant with an increase of ciliary Smo levels [27, 28]. "
    [Show abstract] [Hide abstract] ABSTRACT: The Hedgehog pathway is a pivotal morphogenic driver during embryonic development and a key regulator of adult stem cell self-renewal. The discovery of resident multipotent vascular stem cells and adventitial progenitors within the vessel wall has transformed our understanding of the origin of medial and neointimal vascular smooth muscle cells (SMCs) during vessel repair in response to injury, lesion formation, and overall disease progression. This review highlights the importance of components of the Hh and Notch signalling pathways within the medial and adventitial regions of adult vessels, their recapitulation following vascular injury and disease progression, and their putative role in the maintenance and differentiation of resident vascular stem cells to vascular lineages from discrete niches within the vessel wall.
    Full-text · Article · Jun 2015
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