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Inhibitory Gli3 Activity Negatively Regulates Wnt/β-Catenin Signaling

2007; Elsevier BV; Volume: 17; Issue: 6 Linguagem: Inglês

10.1016/j.cub.2007.01.062

1879-0445

Fausto Ulloa, Nobue Itasaki, James Briscoe,

Developmental Biology and Gene Regulation

The Hedgehog (Hh) and Wingless (Wnt) families of secreted signaling molecules have key roles in embryonic development and adult tissue homeostasis [1Ingham P.W. McMahon A.P. Hedgehog signaling in animal development: paradigms and principles.Genes Dev. 2001; 15: 3059-3087Crossref PubMed Scopus (2332) Google Scholar, 2Logan C.Y. Nusse R. The Wnt signaling pathway in development and disease.Annu. Rev. Cell Dev. Biol. 2004; 20: 781-810Crossref PubMed Scopus (3969) Google Scholar, 3Taipale J. Beachy P.A. The Hedgehog and Wnt signalling pathways in cancer.Nature. 2001; 411: 349-354Crossref PubMed Scopus (1128) Google Scholar]. In the developing neural tube, Wnt and Shh, emanating from dorsal and ventral regions, respectively, have been proposed to govern the proliferation and survival of neural progenitors [4Zechner D. Fujita Y. Hulsken J. Muller T. Walther I. Taketo M.M. Crenshaw 3rd, E.B. Birchmeier W. Birchmeier C. β-Catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system.Dev. Biol. 2003; 258: 406-418Crossref PubMed Scopus (388) Google Scholar, 5Megason S.G. McMahon A.P. A mitogen gradient of dorsal midline Wnts organizes growth in the CNS.Development. 2002; 129: 2087-2098Crossref PubMed Google Scholar, 6Rowitch D.H. S-Jacques B. Lee S.M. Flax J.D. Snyder E.Y. McMahon A.P. Sonic hedgehog regulates proliferation and inhibits differentiation of CNS precursor cells.J. Neurosci. 1999; 19: 8954-8965Crossref PubMed Google Scholar, 7Chiang C. Litingtung Y. Lee E. Young K.E. Corden J.L. Westphal H. Beachy P.A. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function.Nature. 1996; 383: 407-413Crossref PubMed Scopus (2457) Google Scholar, 8Litingtung Y. Chiang C. Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3.Nat. Neurosci. 2000; 3: 979-985Crossref PubMed Scopus (325) Google Scholar, 9Britto J. Tannahill D. Keynes R. A critical role for sonic hedgehog signaling in the early expansion of the developing brain.Nat. Neurosci. 2002; 5: 103-110Crossref PubMed Scopus (101) Google Scholar, 10Cayuso J. Ulloa F. Cox B. Briscoe J. Marti E. The Sonic hedgehog pathway independently controls the patterning, proliferation and survival of neuroepithelial cells by regulating Gli activity.Development. 2006; 133: 517-528Crossref PubMed Scopus (133) Google Scholar]. Surprisingly, Shh is required for the growth and survival of cells in both ventral and dorsal neural tube [11Borycki A.G. Brunk B. Tajbakhsh S. Buckingham M. Chiang C. Emerson Jr., C.P. Sonic hedgehog controls epaxial muscle determination through Myf5 activation.Development. 1999; 126: 4053-4063PubMed Google Scholar]. Here we demonstrate that inhibition of Shh signaling causes a reduction in Wnt-mediated transcriptional activation. This reduction requires Gli3. Assays in embryos and cell lines indicate that repressor forms of the Hh-regulated transcription factor, Gli3 (Gli3R), which are generated in the absence of Hh signaling, inhibit canonical Wnt signaling. Gli3R acts by antagonizing active forms of the Wnt transcriptional effector, β-catenin. Consistent with this, Gli3R appears to physically interact with the carboxy-terminal domain of β-catenin, a region that includes the transactivation domain. These data offer an explanation for the proliferative defects in Shh null embryos and suggest a novel mechanism for crosstalk between the Hh and Wnt pathways.