120, 385C393 [PubMed] [Google Scholar] 43. between DESCs KSHV ORF26 antibody and adjacent dental stromal cells controls DESC self-renewal and expansion and the AZ191 generation of ameloblasts or other lineages of tooth epithelial cells is not well understood. The fibroblast growth factor (FGF) and FGF receptor (FGFR) families have been AZ191 shown to constitute reciprocal regulatory communication loops between the epithelial and mesenchymal compartments, playing important roles in tooth formation and regeneration (10C14). The FGF family consists of 18 receptor-binding members that regulate a broad spectrum of cellular activities (15). The FGF has been AZ191 implicated in tooth morphogenesis via the activation of FGFR tyrosine kinases encoded by four highly homologous genes. In the tooth, the FGF and its cognate FGFR isoforms are expressed in a highly spatiotemporal-specific manner and constitute a directional regulatory axis between the mesenchymal and epithelial compartments. On the one hand, FGF4, -8, and -9 are expressed in the epithelium and function redundantly in regulating adjacent mesenchymal cell proliferation and/or preventing apoptosis (16). On the other hand, and are exclusively expressed in dental mesenchymal cells and promote proliferation of dental epithelial cells in the CL (5, 10, 17). Mice deficient in FGF10 fail to develop incisor CL (11); however, it is not clear whether FGF10 is specifically required to maintain DESCs or the DESC niche. Recent lineage tracing experiments show that the Sox2-positive DESCs give rise to multiple lineages of tooth epithelial cells. Interestingly, FGF8, instead of FGF10, is required for Sox2 expression in the CL (18). The cognate receptors for FGF3 and FGF10, and isoforms, are expressed in the dental epithelium (19). Ablation of in dental epithelial cells affects enamel formation without disrupting ameloblast differentiation (20). AZ191 Disruption of stops tooth development at the budding stage (21). Suppression of FGFR2 signaling during embryonic stages leads to abnormal development of the labial CL and the inner enamel epithelial layer. However, expression of the same mutant in the postnatal stage impairs incisor enamel formation, accompanied by decreased proliferation of the transit amplifying cells, and leads to degradation of the incisors in a reversible manner (14). Loss-of-function mutation of Sprouty, a negative feedback regulator of FGFR and other receptor tyrosine kinases, leads to an increase in tooth numbers, ectopic ameloblast differentiation, and enamel formation in lingual CLs (12, 22C24). All of these results demonstrate the importance and tight regulation of FGF signaling in tooth development. However, how FGF signaling regulates the self-renewal and differentiation of DESCs is not well understood. We reported earlier that tissue-specific ablation of in dental epithelial cells leads to severe defects in maxillary incisors that lack ameloblasts and enamel, as well as having poorly developed odontoblasts (13). Although the CL in conditional null maxillary incisors is formed initially, it fails to continue to develop and gradually diminishes soon after birth, suggesting that FGFR2 signaling is essential for maintaining the DESC niche required for incisor development and lifelong growth. Here we further report that using the newly developed DESC sphere culture method (9), it was found that FGF signaling was critical for the sphere forming capacity of the DESCs, which is normally used to evaluate the self-renewal activity of SCs (25C27). FGF2 promoted the sphere forming activity of the DESCs, and suppression of FGFR,.