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

Developmental Biology Program, Sloan-Kettering Institute, 1275 York Avenue, New York, NY 10065, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2009; 106(32):13377-82. 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.

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    • "Although being the mammalian homolog of Drosophila Cos2, the essential upstream signalling component Ci, the involvement of Kif7 in HH signalling was not established until fairly recently [22]–[24]. Kif7 knock-out mice exhibited exencephaly and polydactyly which are phenotypes reminiscent of Gli3 knockout, suggesting that Kif7 predominantly acts as a suppressor of HH signalling during development [23], [24]. Our findings that Kif7 is downregulated imply that HH signalling is activated in CCA. "
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    ABSTRACT: The kinesin protein Kif7 has been recognized as an integral component of hedgehog signalling. Aberrant activation of hedgehog signalling has been implicated in many human solid tumours. Gestational trophoblastic disease includes frankly malignant choriocarcinoma and potentially malignant hydatidiform mole. Here we investigated the hedgehog signalling components expression profiles in gestational trophoblastic disease. Downregulation of Gli1, Gli2, Gli3 and Kif7 was demonstrated in clinical samples of choriocarcinoma and hydatidiform moles as well as choriocarcinoma cell lines when compared with normal placentas. Ectopic expression of Kif7 in two choriocarcinoma cell lines JAR and JEG-3 led to a decrease in cell growth and increase in apoptosis demonstrated by MTT and TUNEL assays, respectively. Overexpression of Kif7 also led to suppressed cell migration through transwell assay. In contrast, knocking down Kif7 in HTR-8/SVneo, an immortalized trophoblast cell line, increased cell number over time and increased the migratory ability of the cells. Taken together, Kif7 may contribute to pathogenesis of gestational trophoblastic disease through enhancing survival and promoting dissemination of trophoblasts.
    PLoS ONE 09/2014; 9(9):e108248. DOI:10.1371/journal.pone.0108248 · 3.23 Impact Factor
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    • "Other phenotypes associated with abnormal Hedgehog signaling include a loss of ventral neuronal patterning in the neural tube of all species, expansion of Eng2 in the zebrafish somite and misprocessing of Gli2 and Gli3 (Bangs et al., 2011; Ben et al., 2011; Davey et al., 2006). The Hedgehog pathway related phenotypes caused by TALPID3 loss of function are similar to mouse mutants with a loss of primary cilia (e.g., Huangfu and Anderson 2005; reviewed Goetz and Anderson, 2010) as the Hedgehog pathway component proteins, Smo and Gli must be transported into the cilia to activate normal Gli protein modification (e.g., Corbit et al., 2005; Haycraft et al., 2005; Liem et al., 2009; Rohatgi et al., 2007). In addition to a loss of Hedgehog pathway function, the talpid 3 chicken develops polycystic kidneys and the targeted deletion of TALPID3 in zebrafish causes a dilation of the pronephric duct (Bangs et al., 2011; Ben et al., 2011). "
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    ABSTRACT: Motile cilia are an essential component of the mouse, zebrafish, and Xenopus laevis Left Right Organizers, generating nodal flow and allowing the reception and transduction of mechanosensory signals. Nonmotile primary cilia are also an important component of the Left Right Organizer's chemosensory mechanism. It has been proposed in the chicken that signaling in Hensen's node, the Left Right Organizer of the chicken, is independent of cilia, based on a lack of evidence of motile cilia or nodal flow. It is speculated that the talpid3 chicken mutant, which has normal left–right patterning despite lacking cilia at many stages of development, is proof of this hypothesis. Here, we examine the evidence for cilia in Hensen's node and find that although cilia are present; they are likely to be immotile and incapable of generating nodal flow. Furthermore, we find that early planar cell polarity patterning and ciliogenesis is normal in early talpid3 chicken embryos. We conclude that patterning and development of the early talpid3 chicken is normal, but not necessarily independent of cilia. Although it appears that Hensen's node does not require motile cilia or the generation of motile flow, there may remain a requirement for cilia in the transduction of SHH signaling. Results FOXJ1 is expressed at low levels in the chicken node incompatible with motile cilia generationShort cilia are present in the mesodermal cells of the chicken nodeTalpid3 chicken embryos have normal VANGL2 localization early in developmentTalpid3 chicken embryos have primary cilia early in development
    genesis 06/2014; 52(6). DOI:10.1002/dvg.22775 · 2.02 Impact Factor
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    • "For example, loss of IFT B complex (e.g. Ift172 ) blocks ciliogenesis and attenuates Kif7 trafficking, such that Kif7 maki ; Ift172 wim double mutants exhibit phenotypes indistinguishable from that of Ift172 wim mutant [Endoh-Yamagami et al., 2009; Liem et al., 2009]. Furthermore , active Smo progressively promotes the dissociation of Gli from Sufu and induces the microtubuledependent translocation of Gli to the nucleus to activate Hh target gene transcription [Humke et al., 2010; Tukachinsky et al., 2010]. "
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    ABSTRACT: Hedgehog (Hh) signaling is vital for the patterning and organogenesis of almost every system. The specificity of these developmental processes is achieved through a tight spatio-temporal regulation of Hh signaling. Mice with defective Hh signal exhibit a wide spectrum of anomalies, including Vertebral defects, Anal atresia, Cardiovascular anomalies, Tracheoesophageal fistula, Renal dysplasia, and Limb defects, that resemble strikingly the phenotypes observed in VACTERL association in humans. In this review, we summarize our current understanding of mammalian Hh signaling and highlight the relevance of various mouse models for studying the etiology and pathogenesis of VACTERL association. In addition, recent advances in genetic study for unraveling the complexity of genetic inheritance of VACTERL and the implication of the Sonic hedgehog pathway in disease pathogenesis are also discussed.
    Molecular syndromology 02/2013; 4(1-2):32-45. DOI:10.1159/000345725
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