We did not observe any effects of Wnt11 on ectodermal cell proliferation at stage 12-14 using antibodies against phospho-histone H3 (data not shown). of the serine/threonine polarity kinase PAR-1 (also known as microtubule-associated regulatory kinase or Tag), which itself plays an essential part in NC formation. Consistent with this model,PAR-1RNA rescues NC markers in embryos in which noncanonical Wnt signaling has been blocked. These experiments identify novel functions for Wnt11R and PAR-1 in NC specification and reveal an unexpected connection between morphogenesis and cell fate. Keywords:Noncanonical Wnt signaling, Neural crest, Dishevelled,Xenopus, PAR-1, Microtubule-associated regulatory kinase, Cell polarity == Intro == The neural crest (NC) comprises stem-cell-like cells that form in vertebrate embryos in the neural plate border, migrate to varied locations in the body and differentiate into multiple cell types (Anderson, 1997;Crane and Trainor, 2006;Knight and Schilling, 2006;Le Douarin and Dupin, 2003;Sauka-Spengler and Bronner-Fraser, 2008). NC GOAT-IN-1 is definitely specified from the combined action of a number of embryonic signaling pathways, including the Wnt, FGF, BMP and Notch pathways, and NC fates are managed by a network of specific transcription factors. Once created, NC cells undergo epithelial-mesenchymal transition (EMT) and migrate to many destinations in the body to contribute to varied cell types, including face cartilage, melanocytes and the peripheral nervous system (Acloque et al., 2009;Heeg-Truesdell and LaBonne, 2004;Kuriyama and Mayor, 2008;Thiery et al., 2009;Yang and Weinberg, 2008). The large number of human diseases that are associated with NC abnormalities, including craniosynostosis, Waardenburg and Hirschsprungs syndromes and cancers, draw considerable attention to studies of the mechanisms of NC development (Crane and Trainor, 2006;Heeg-Truesdell and LaBonne, 2004). One pathway that is essential for NC specification in all vertebrate models examined is the Wnt pathway. Canonical Wnt signaling activates -catenin/TCF-dependent gene transcription and regulates cell proliferation and cell fate (Cadigan and Peifer, 2009;Clevers, 2006). The involvement of this pathway in NC formation was first established by genetic studies ofWnt1/Wnt3adouble-knockout mice and in gain-of-function experiments inXenopus(Ikeya et al., 1997;Saint-Jeannet et al., 1997), and was consequently extended GOAT-IN-1 to additional models (Dorsky et al., 1998;Garcia-Castro et al., 2002;Hari et al., 2002;Lewis et al., 2004;Wu et al., 2003). The transcription of many NC-specific genes, includingSnail2, SnailandTwist, offers been shown to depend on -catenin/TCF (Garcia-Castro et al., 2002;Howe et al., 2003;LaBonne, 2002;Sauka-Spengler and Bronner-Fraser, 2008;Vallin et al., 2001;Wu et al., 2003), further assisting the model that NC formation entails the Wnt/-catenin pathway. Noncanonical Wnt ligands, such as Wnt5a and Wnt11 (Angers and Moon, 2009;van Amerongen and Nusse, 2009), do not stabilize -catenin or activate TCF-dependent transcription, but regulate morphogenetic processes that involve changes in cell shape and motility, which are sometimes referred to as planar cell GOAT-IN-1 polarity (PCP) (Ciani and Salinas, 2005;Komiya and Habas, 2008;Saneyoshi et al., 2002;van Amerongen et al., 2008;Winklbauer et al., 2001). The signaling from Wnt5 or Wnt11 is definitely thought to involve Ror and Ryk receptors (Grumolato et al., 2010;Hikasa et al., 2002a;Lin et al., 2010;Lu et al., 2004;Mikels et al., 2009;Minami et al., 2010), small Rho GTPases (Habas et al., 2003;Habas et al., 2001), Rho-associated kinase (Marlow et al., 2002;Winter season et al., 2001), c-Jun N-terminal kinases (Boutros et al., 1998;Lisovsky et al., 2002;Pandur et al., 2002) and intracellular calcium (Sheldahl et al., 2003;Slusarski et al., 1997;Witze et al., 2008). Although noncanonical Wnt pathways have been shown to function in NC cell migration (Carmona-Fontaine et al., 2008;De Calisto et al., 2005;Matthews et al., 2008b), their importance for NC specification has remained unclear. Craniofacial problems inWnt5aknockout mice (Yamaguchi et al., 1999), and inwnt11(silberblick) (Heisenberg et al., 2000;Heisenberg et al., 1996) andwnt5(pipetail) IL5RA (Piotrowski GOAT-IN-1 et al., 1996) zebrafish mutant embryos suggest possible functions for noncanonical Wnt signaling in NC development. The results of our study support the look at GOAT-IN-1 that noncanonical signaling from Wnt11R is essential for NC specification inXenopusembryos and that it might work by.
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