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By genetic mapping, sequence analysis of candidate genes and characterization of a second mutant allele, we identify Hty as C2cd3, a novel gene encoding a vertebrate-specific C2 domain-containing protein. Target gene expression and double-mutant analyses suggest that C2cd3 is an essential regulator of intracellular transduction of the Hedgehog signal. Furthering a link between Hedgehog signaling and cilia function, we find that cilia formation and proteolytic processing of Gli3 are disrupted in C2cd3 mutants. Finally, we observe C2cd3 protein at the basal body, consistent with its essential function in ciliogenesis. Interestingly, the human ortholog for this gene lies in proximity to the critical regions of Meckel-Gruber syndrome 2 (MKS2) and Joubert syndrome 2 (JBTS2), making it a potential candidate for these two human genetic disorders.<\/jats:p>","DOI":"10.1242\/dev.029835","type":"journal-article","created":{"date-parts":[[2008,11,13]],"date-time":"2008-11-13T01:24:57Z","timestamp":1226539497000},"page":"4049-4058","source":"Crossref","is-referenced-by-count":95,"title":["C2cd3 is required for cilia formation and Hedgehog signaling in mouse"],"prefix":"10.1242","volume":"135","author":[{"given":"Amber N.","family":"Hoover","sequence":"first","affiliation":[{"name":"Department of Biology, Eberly College of Science, The Pennsylvania State University, 201 Life Science Building, University Park, PA 16802, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Wynkoop","sequence":"additional","affiliation":[{"name":"Department of Biology, Eberly College of Science, The Pennsylvania State University, 201 Life Science Building, University Park, PA 16802, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiqing","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Biology, Eberly College of Science, The Pennsylvania State University, 201 Life Science Building, University Park, PA 16802, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinping","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Biology, Eberly College of Science, The Pennsylvania State University, 201 Life Science Building, University Park, PA 16802, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee A.","family":"Niswander","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Department of Pediatrics, University of Colorado Health Sciences Center, 12800 E. 19th Avenue, Aurora, CO 80045,USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aimin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biology, Eberly College of Science, The Pennsylvania State University, 201 Life Science Building, University Park, PA 16802, USA."},{"name":"The Programs of Cell and Developmental Biology, Genetics and Neuroscience,Huck Institutes of the Life Sciences, The Pennsylvania State University, 201 Life Science Building, University Park, PA 16802, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042621244427800_REF1","doi-asserted-by":"crossref","unstructured":"Bai, C. B., Stephen, D. and Joyner, A. L.(2004). All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Dev. Cell6,103-115.","DOI":"10.1016\/S1534-5807(03)00394-0"},{"key":"2021042621244427800_REF2","doi-asserted-by":"crossref","unstructured":"Bisgrove, B. W. and Yost, H. J. (2006). The roles of cilia in developmental disorders and disease. Development133,4131-4143.","DOI":"10.1242\/dev.02595"},{"key":"2021042621244427800_REF3","doi-asserted-by":"crossref","unstructured":"Chiang, C., Litingtung, Y., Lee, E., Young, K. E., Corden, J. L., Westphal, H. and Beachy, P. A. (1996). Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature383,407-413.","DOI":"10.1038\/383407a0"},{"key":"2021042621244427800_REF4","doi-asserted-by":"crossref","unstructured":"Chuang, P. T. and McMahon, A. P. (1999). Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature397,617-621.","DOI":"10.1038\/17611"},{"key":"2021042621244427800_REF5","doi-asserted-by":"crossref","unstructured":"Collignon, J., Varlet, I. and Robertson, E. J.(1996). Relationship between asymmetric nodal expression and the direction of embryonic turning. Nature381,155-158.","DOI":"10.1038\/381155a0"},{"key":"2021042621244427800_REF6","doi-asserted-by":"crossref","unstructured":"Corbit, K. C., Aanstad, P., Singla, V., Norman, A. R., Stainier,D. Y. and Reiter, J. F. (2005). Vertebrate Smoothened functions at the primary cilium. Nature437,1018-1021.","DOI":"10.1038\/nature04117"},{"key":"2021042621244427800_REF7","doi-asserted-by":"crossref","unstructured":"Eggenschwiler, J. T. and Anderson, K. V.(2000). Dorsal and lateral fates in the mouse neural tube require the cell-autonomous activity of the open brain gene. Dev. Biol.227,648-660.","DOI":"10.1006\/dbio.2000.9918"},{"key":"2021042621244427800_REF8","doi-asserted-by":"crossref","unstructured":"Eggenschwiler, J. T., Espinoza, E. and Anderson, K. V.(2001). Rab23 is an essential negative regulator of the mouse Sonic hedgehog signalling pathway. Nature412,194-198.","DOI":"10.1038\/35084089"},{"key":"2021042621244427800_REF9","doi-asserted-by":"crossref","unstructured":"Eggenschwiler, J. T., Bulgakov, O. V., Qin, J., Li, T. and Anderson, K. V. (2006). Mouse Rab23 regulates hedgehog signaling from smoothened to Gli proteins. Dev. Biol.290, 1-12.","DOI":"10.1016\/j.ydbio.2005.09.022"},{"key":"2021042621244427800_REF10","doi-asserted-by":"crossref","unstructured":"Fliegauf, M., Benzing, T. and Omran, H. (2007). When cilia go bad: cilia defects and ciliopathies. Nat. Rev. Mol. Cell Biol.8,880-893.","DOI":"10.1038\/nrm2278"},{"key":"2021042621244427800_REF11","doi-asserted-by":"crossref","unstructured":"Gherman, A., Davis, E. E. and Katsanis, N.(2006). The ciliary proteome database: an integrated community resource for the genetic and functional dissection of cilia. Nat. Genet.38,961-962.","DOI":"10.1038\/ng0906-961"},{"key":"2021042621244427800_REF12","doi-asserted-by":"crossref","unstructured":"Goodrich, L. V., Milenkovic, L., Higgins, K. M. and Scott, M. P. (1997). Altered neural cell fates and medulloblastoma in mouse patched mutants. Science277,1109-1113.","DOI":"10.1126\/science.277.5329.1109"},{"key":"2021042621244427800_REF13","doi-asserted-by":"crossref","unstructured":"Han, Y. G., Kwok, B. H. and Kernan, M. J.(2003). Intraflagellar transport is required in Drosophila to differentiate sensory cilia but not sperm. Curr. Biol.13,1679-1686.","DOI":"10.1016\/j.cub.2003.08.034"},{"key":"2021042621244427800_REF14","doi-asserted-by":"crossref","unstructured":"Haycraft, C. J., Banizs, B., Aydin-Son, Y., Zhang, Q., Michaud,E. J. and Yoder, B. K. (2005). Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet.1, e53.","DOI":"10.1371\/journal.pgen.0010053"},{"key":"2021042621244427800_REF15","doi-asserted-by":"crossref","unstructured":"Hooper, J. E. and Scott, M. P. (2005). Communicating with Hedgehogs. Nat. Rev. Mol. Cell Biol.6,306-317.","DOI":"10.1038\/nrm1622"},{"key":"2021042621244427800_REF16","doi-asserted-by":"crossref","unstructured":"Huangfu, D. and Anderson, K. V. (2005). Cilia and Hedgehog responsiveness in the mouse. Proc. Natl. Acad. Sci. USA102,11325-11330.","DOI":"10.1073\/pnas.0505328102"},{"key":"2021042621244427800_REF17","doi-asserted-by":"crossref","unstructured":"Huangfu, D., Liu, A., Rakeman, A. S., Murcia, N. S., Niswander,L. and Anderson, K. V. (2003). Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature426,83-87.","DOI":"10.1038\/nature02061"},{"key":"2021042621244427800_REF18","doi-asserted-by":"crossref","unstructured":"Inglis, P. N., Boroevich, K. A. and Leroux, M. R.(2006). Piecing together a ciliome. Trends Genet.22,491-500.","DOI":"10.1016\/j.tig.2006.07.006"},{"key":"2021042621244427800_REF19","doi-asserted-by":"crossref","unstructured":"Karcher, C., Fischer, A., Schweickert, A., Bitzer, E., Horie,S., Witzgall, R. and Blum, M. (2005). Lack of a laterality phenotype in Pkd1 knock-out embryos correlates with absence of polycystin-1 in nodal cilia. Differentiation73,425-432.","DOI":"10.1111\/j.1432-0436.2005.00048.x"},{"key":"2021042621244427800_REF20","doi-asserted-by":"crossref","unstructured":"Liu, A., Joyner, A. L. and Turnbull, D. H.(1998). Alteration of limb and brain patterning in early mouse embryos by ultrasound-guided injection of Shh-expressing cells. Mech. Dev.75,107-115.","DOI":"10.1016\/S0925-4773(98)00090-2"},{"key":"2021042621244427800_REF21","doi-asserted-by":"crossref","unstructured":"Liu, A., Losos, K. and Joyner, A. L. (1999). FGF8 can activate Gbx2 and transform regions of the rostral mouse brain into a hindbrain fate. Development126,4827-4838.","DOI":"10.1242\/dev.126.21.4827"},{"key":"2021042621244427800_REF22","doi-asserted-by":"crossref","unstructured":"Liu, A., Wang, B. and Niswander, L. A. (2005). Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development132,3103-3111.","DOI":"10.1242\/dev.01894"},{"key":"2021042621244427800_REF23","doi-asserted-by":"crossref","unstructured":"McGrath, J., Somlo, S., Makova, S., Tian, X. and Brueckner,M. (2003). Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell114, 61-73.","DOI":"10.1016\/S0092-8674(03)00511-7"},{"key":"2021042621244427800_REF24","doi-asserted-by":"crossref","unstructured":"Meno, C., Saijoh, Y., Fujii, H., Ikeda, M., Yokoyama, T.,Yokoyama, M., Toyoda, Y. and Hamada, H. (1996). Left-right asymmetric expression of the TGF beta-family member lefty in mouse embryos. Nature381,151-155.","DOI":"10.1038\/381151a0"},{"key":"2021042621244427800_REF25","doi-asserted-by":"crossref","unstructured":"Methot, N. and Basler, K. (2001). An absolute requirement for Cubitus interruptus in Hedgehog signaling. Development128,733-742.","DOI":"10.1242\/dev.128.5.733"},{"key":"2021042621244427800_REF26","doi-asserted-by":"crossref","unstructured":"Nachury, M. V., Loktev, A. V., Zhang, Q., Westlake, C. J.,Peranen, J., Merdes, A., Slusarski, D. C., Scheller, R. H., Bazan, J. F.,Sheffield, V. C. et al. (2007). A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell129,1201-1213.","DOI":"10.1016\/j.cell.2007.03.053"},{"key":"2021042621244427800_REF27","doi-asserted-by":"crossref","unstructured":"Nalefski, E. A. and Falke, J. J. (1996). The C2 domain calcium-binding motif: structural and functional diversity. 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Invest.85,452-463.","DOI":"10.1038\/labinvest.3700253"},{"key":"2021042621244427800_REF31","doi-asserted-by":"crossref","unstructured":"Pan, Y., Bai, C. B., Joyner, A. L. and Wang, B.(2006). Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol. Cell. Biol.26,3365-3377.","DOI":"10.1128\/MCB.26.9.3365-3377.2006"},{"key":"2021042621244427800_REF32","doi-asserted-by":"crossref","unstructured":"Praetorius, H. A. and Spring, K. R. (2001). Bending the MDCK cell primary cilium increases intracellular calcium. J. Membr. Biol.184,71-79.","DOI":"10.1007\/s00232-001-0075-4"},{"key":"2021042621244427800_REF33","doi-asserted-by":"crossref","unstructured":"Raya, A., Kawakami, Y., Rodriguez-Esteban, C., Ibanes, M.,Rasskin-Gutman, D., Rodriguez-Leon, J., Buscher, D., Feijo, J. A. and Izpisua Belmonte, J. C. (2004). Notch activity acts as a sensor for extracellular calcium during vertebrate left-right determination. Nature427,121-128.","DOI":"10.1038\/nature02190"},{"key":"2021042621244427800_REF34","doi-asserted-by":"crossref","unstructured":"Rohatgi, R., Milenkovic, L. and Scott, M. P.(2007). Patched1 regulates hedgehog signaling at the primary cilium. Science317,372-376.","DOI":"10.1126\/science.1139740"},{"key":"2021042621244427800_REF35","doi-asserted-by":"crossref","unstructured":"Rosenbaum, J. L. and Witman, G. B. (2002). Intraflagellar transport. Nat. Rev. Mol. Cell Biol.3, 813-825.","DOI":"10.1038\/nrm952"},{"key":"2021042621244427800_REF36","doi-asserted-by":"crossref","unstructured":"Roume, J., Genin, E., Cormier-Daire, V., Ma, H. W., Mehaye, B.,Attie, T., Razavi-Encha, F., Fallet-Bianco, C., Buenerd, A., Clerget-Darpoux,F. et al. (1998). A gene for Meckel syndrome maps to chromosome 11q13. Am. J. Hum. Genet.63,1095-1101.","DOI":"10.1086\/302062"},{"key":"2021042621244427800_REF37","doi-asserted-by":"crossref","unstructured":"Sarpal, R., Todi, S. V., Sivan-Loukianova, E., Shirolikar, S.,Subramanian, N., Raff, E. C., Erickson, J. W., Ray, K. and Eberl, D. F.(2003). Drosophila KAP interacts with the kinesin II motor subunit KLP64D to assemble chordotonal sensory cilia, but not sperm tails. Curr. Biol.13,1687-1696.","DOI":"10.1016\/j.cub.2003.09.025"},{"key":"2021042621244427800_REF38","doi-asserted-by":"crossref","unstructured":"Tanaka, Y., Okada, Y. and Hirokawa, N. (2005). FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal flow is critical for left-right determination. Nature435,172-177.","DOI":"10.1038\/nature03494"},{"key":"2021042621244427800_REF39","doi-asserted-by":"crossref","unstructured":"Tobin, J. L., Di Franco, M., Eichers, E., May-Simera, H.,Garcia, M., Yan, J., Quinlan, R., Justice, M. J., Hennekam, R. C., Briscoe, J. et al. (2008). Inhibition of neural crest migration underlies craniofacial dysmorphology and Hirschsprung's disease in Bardet-Biedl syndrome. Proc. Natl. Acad. Sci. USA105,6714-6719.","DOI":"10.1073\/pnas.0707057105"},{"key":"2021042621244427800_REF40","doi-asserted-by":"crossref","unstructured":"Valente, E. M., Marsh, S. E., Castori, M., Dixon-Salazar, T.,Bertini, E., Al-Gazali, L., Messer, J., Barbot, C., Woods, C. G., Boltshauser,E. et al. (2005). Distinguishing the four genetic causes of Jouberts syndrome-related disorders. Ann. Neurol.57,513-519.","DOI":"10.1002\/ana.20422"},{"key":"2021042621244427800_REF41","doi-asserted-by":"crossref","unstructured":"Wallingford, J. B., Ewald, A. J., Harland, R. M. and Fraser, S. E. (2001). Calcium signaling during convergent extension in Xenopus. Curr. Biol.11,652-661.","DOI":"10.1016\/S0960-9822(01)00201-9"},{"key":"2021042621244427800_REF42","doi-asserted-by":"crossref","unstructured":"Wang, B., Fallon, J. F. and Beachy, P. A.(2000). Hedgehog-regulated processing of Gli3 produces an anterior\/posterior repressor gradient in the developing vertebrate limb. Cell100,423-434.","DOI":"10.1016\/S0092-8674(00)80678-9"},{"key":"2021042621244427800_REF43","doi-asserted-by":"crossref","unstructured":"Webb, S. E. and Miller, A. L. (2006). Ca2+signaling and early embryonic patterning during the blastula and gastrula periods of zebrafish and Xenopus development. Biochim. Biophys. Acta1763,1192-1208.","DOI":"10.1016\/j.bbamcr.2006.08.004"},{"key":"2021042621244427800_REF44","doi-asserted-by":"crossref","unstructured":"Wilson, P. D. (2004). Polycystic kidney disease: new understanding in the pathogenesis. Int. J. Biochem. Cell Biol.36,1868-1873.","DOI":"10.1016\/j.biocel.2004.03.012"},{"key":"2021042621244427800_REF45","doi-asserted-by":"crossref","unstructured":"Witman, G. B. (2003). Cell motility: deaf Drosophila keep the beat. Curr. Biol.13,R796-R798.","DOI":"10.1016\/j.cub.2003.09.047"},{"key":"2021042621244427800_REF46","doi-asserted-by":"crossref","unstructured":"Zohn, I. E., Anderson, K. V. and Niswander, L.(2005). Using genomewide mutagenesis screens to identify the genes required for neural tube closure in the mouse. Birth Defects Res. Part A Clin. Mol. 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