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: 9.81). 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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    • "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 Organisers, generating nodal flow and allowing the reception and transduction of mechanosensory signals. Non-motile primary cilia are also an important component of the Left Right Organiser's chemosensory mechanism. It has been proposed in the chicken that signalling in Hensen's node, the Left Right Organiser 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. While 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 signalling.Results• FOXJ1 is expressed at low levels in the chicken node incompatible with motile cilia generation• Short cilia are present in the mesodermal cells of the chicken node• Talpid3 chicken embryos have normal VANGL2 localisation early in development• Talpid3 chicken embryos have primary cilia early in development © 2014 Wiley Periodicals, Inc.
    genesis 06/2014; 52(6). DOI:10.1002/dvg.22775 · 2.04 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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    • "Genetic studies in mice revealed both positive and negative regulatory roles for Kif7 in Hh signaling, similar to Cos2 (Cheung et al. 2009; Endoh-Yamagami et al. 2009; Liem et al. 2009). Though the precise relationship between Smo and Kif7 remains to be elucidated, it has been noted that Kif7 accumulates in the primary cilium when over-expressed and that its action may require this organelle (Endoh-Yamagami et al. 2009; Liem et al. 2009). Mouse genetics suggest the mammalian homo log of the fly serine/threonine kinase Fu does not play a critical role in Hh signal transduction (Chen et al. 2005; Merchant et al. 2005). "
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    ABSTRACT: The Hedgehog (Hh) pathway is essential for vertebrate embryogenesis, and excessive Hh target gene activation can cause cancer in humans. Here we show that Neuropilin 1 (Nrp1) and Nrp2, transmembrane proteins with roles in axon guidance and vascular endothelial growth factor (VEGF) signaling, are important positive regulators of Hh signal transduction. Nrps are expressed at times and locations of active Hh signal transduction during mouse development. Using cell lines lacking key Hh pathway components, we show that Nrps mediate Hh transduction between activated Smoothened (Smo) protein and the negative regulator Suppressor of Fused (SuFu). Nrp1 transcription is induced by Hh signaling, and Nrp1 overexpression increases maximal Hh target gene activation, indicating the existence of a positive feedback circuit. The regulation of Hh signal transduction by Nrps is conserved between mammals and bony fish, as we show that morpholinos targeting the Nrp zebrafish ortholog nrp1a produce a specific and highly penetrant Hh pathway loss-of-function phenotype. These findings enhance our knowledge of Hh pathway regulation and provide evidence for a conserved nexus between Nrps and this important developmental signaling system.
    Genes & development 11/2011; 25(22):2333-46. DOI:10.1101/gad.173054.111 · 12.64 Impact Factor
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