A variety of craniofacial organs and tissues, such as the Meckel’s cartilage, maxillary and mandible bone, trigeminal ganglion and dentin-producing odontoblasts, derive from craniofacial neural crest

INTRODUCTION A variety of craniofacial organs and tissues, such as the Meckel’s cartilage, maxillary and mandible bone, trigeminal ganglion and dentin-producing odontoblasts, derive from craniofacial neural crest cells (Chai et al., 2000; Chung et al., 2009). Despite originating from the same progenitor population, craniofacial bone and tooth exhibit distinct developmental, morphological and histological characteristics (Lumsden, 1988; D’Souza et al., 1999; Chai et al., 2000; Zhang et al., 2005; James et al., 2006). It is well established that multiple signaling pathways, including Wnt, TGFβ/BMP, Hh and FGF signaling, are involved in regulating every step of tooth development (Thesleff and Mikkola, 2002; Tummers and Thesleff, 2009), but the mechanisms that specify and ensure the odontogenic fate in dental mesenchyme remain largely unknown. FGF signaling has been implicated in regulating tooth development at several distinct steps. FGF signaling might be involved in the specification of odontogenic fate in both dental epithelial and dental mesenchyme, as evidenced by Fgf8 expression in the presumptive dental epithelium and its induction of Pitx2 and Pax9, the earliest molecular markers of the dental epithelium and mesenchyme, respectively, to determine the tooth-forming site (Neubüser et al., 1997; Trumpp et al., 1999; St Amand et al., 2000). At the bud stage, epithelial FGF4 and FGF8 are likely to activate Fgf3 in the dental mesenchyme through the mediation of Msx1 and Runx2, and FGF3 in turn, possibly together with FGF10, acts back on the dental epithelium to induce/maintain Shh expression in the enamel knot (Bei and Maas, 1998; Kettunen et al., 2000; Aberg et al., 2004). At the cap stage, expression of several FGFs in the enamel knot stimulates cell proliferation in the dental epithelium, leading to epithelial folding and cusp patterning (Jernvall et al., 1994; Jernvall and Thesleff, 2000). Furthermore, releasing FGF signaling from suppression by Sprouty factors leads to tooth formation in the diastema region, indicating a potential role for FGF signaling in the regulation of odontogenic fate (Klein et al., 2006; Li et al., 2011b). The essential role of canonical Wnt (Wnt/β-catenin) signaling in tooth development has been well documented (Liu and Millar, 2010). Many Wnt ligands are expressed in the developing tooth, predominantly in the epithelial component, with WNT5A, a noncanonical Wnt, in the mesenchyme (Dassule and McMahon, 1998; Sarkar and Sharpe, 1999). These Wnt ligands appear to act in both intraand intertissue manners to regulate tooth development. Epithelial deletion of Catnb (Ctnnb1 – Mouse Genome Informatics), the gene encoding β-catenin, or Gpr177 (Wls – Mouse Genome Informatics), the product of which is required for secretion of Wnts, leads to an arrest of tooth development at the bud or early cap stage (Liu et al., 2008; Zhu et al., 2013). A similar developmental defect was also observed in mice lacking Catnb in the dental mesenchyme (Chen et al., 2009). Conversely, constitutive activation of β-catenin signaling in oral epithelium induces ectopic tooth formation (Järvinen et al., 2006; Liu et al., 2008). Although βcatenin signaling activity is present in the dental mesenchyme of the E12.5 incisor (Fujimori et al., 2010), such activity has never been reported in the incisor mesenchyme beyond E12.5 and was not detected in developing molar mesenchyme using several Wnt/βcatenin signaling reporter mouse lines, including BATGAL, TOPGAL and TCF/Lef-lacZ mice (Liu et al., 2008), suggesting that Wnt/β-catenin activity is maintained at a very low level, if any, in the dental mesenchyme. Elevated Wnt/β-catenin signaling results in the formation of bone-like tissues in the dental pulp (Chen et al., 2009; Li et al., 2011a). Thus, a finely tuned level of Wnt/β-catenin signaling is essential for proper tooth development. 1Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA. 2College of Life Science, Fujian Normal University, Fuzhou, Fujian Province 350108, P.R. China.