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


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.
    Full-text · Article · Sep 2014 · PLoS ONE
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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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    Full-text · Article · Jun 2014 · genesis
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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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