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Background  Analyses of  Fgf10  and  Fgfr2b  mutant mice, as well as human studies, suggest that FGF10/FGFR2b signaling may play an essential, nonredundant role during embryonic SMG development. To address this question, we have analyzed the SMG phenotype in  Fgf10  and  Fgfr2b  heterozygous and null mutant mice. In addition, although previous studies suggest that the FGF10/FGFR2b and FGF8/FGFR2c signaling pathways are functionally interrelated, little is known about the functional relationship between these two pathways during SMG development. We have designed  in vivo  and  in vitro  experiments to address this question.    Results  We analyzed  Fgf10  and  Fgfr2b  heterozygous mutant and null mice and demonstrate dose-dependent SMG phenotypic differences. Hypoplastic SMGs are seen in  Fgf10  and  Fgfr2b  heterozygotes whereas SMG aplasia is seen in  Fgf10  and  Fgfr2b  null embryos. Complementary  in vitro  studies further indicate that FGF10/FGFR2b signaling regulates SMG epithelial branching and cell proliferation. To delineate the functional relationship between the FGF10/FGFR2b and FGF8/FGFR2c pathways, we compared the SMG phenotype in  Fgfr2c  +/ Δ   /Fgf10  +/-  double heterozygous mice to that seen in wildtype,  Fgf10  +/-  ( Fgfr2c  +/+  /Fgf10  +/- ) and  Fgfr2c  +/ Δ   ( Fgfr2c  +/ Δ   /Fgf10  +/+ ) single heterozygous mutant littermates and demonstrate genotype-specific SMG phenotypes. In addition, exogenous FGF8 was able to rescue the abnormal SMG phenotype associated with abrogated FGFR2b signaling  in vitro  and restore branching to normal levels.    Conclusion  Our data indicates that FGF10/FGFR2b signaling is essential for the SMG epithelial branching and histodifferentiation, but not earliest initial bud formation. The functional presence of other endogenous signaling pathways could not prevent complete death of embryonic SMG cells in  Fgf10  and  Fgfr2b  null mice. Though we were able to rescue the abnormal phenotype associated with reduced  in vitro  FGF10/FGFR2b signaling with exogenous FGF8 supplementation, our results indicate that the FGF10/FGFR2b and FGF8/FGFR2c are nonredundant signaling pathways essential for  in vivo  embryonic SMG development. What remains to be determined is the  in vivo  functional relationship between the FGF10/FGFR2b signal transduction pathway and other key signaling pathways, and how these pathways are integrated during embryonic SMG development to compose the functional epigenome.

FGF10/FGFR2b signaling plays essential roles during in vivo embryonic submandibular salivary gland morphogenesis