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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<jats:italic>in vivo<\/jats:italic>and<jats:italic>in vitro<\/jats:italic>experiments to address this question.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We analyzed<jats:italic>Fgf10<\/jats:italic>and<jats:italic>Fgfr2b<\/jats:italic>heterozygous mutant and null mice and demonstrate dose-dependent SMG phenotypic differences. Hypoplastic SMGs are seen in<jats:italic>Fgf10<\/jats:italic>and<jats:italic>Fgfr2b<\/jats:italic>heterozygotes whereas SMG aplasia is seen in<jats:italic>Fgf10<\/jats:italic>and<jats:italic>Fgfr2b<\/jats:italic>null embryos. Complementary<jats:italic>in vitro<\/jats:italic>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<jats:italic>Fgfr2c<\/jats:italic><jats:sup>+\/<jats:italic>\u0394<\/jats:italic><\/jats:sup><jats:italic>\/Fgf10<\/jats:italic><jats:sup>+\/-<\/jats:sup>double heterozygous mice to that seen in wildtype,<jats:italic>Fgf10<\/jats:italic><jats:sup>+\/-<\/jats:sup>(<jats:italic>Fgfr2c<\/jats:italic><jats:sup>+\/+<\/jats:sup><jats:italic>\/Fgf10<\/jats:italic><jats:sup>+\/-<\/jats:sup>) and<jats:italic>Fgfr2c<\/jats:italic><jats:sup>+\/<jats:italic>\u0394<\/jats:italic><\/jats:sup>(<jats:italic>Fgfr2c<\/jats:italic><jats:sup>+\/<jats:italic>\u0394<\/jats:italic><\/jats:sup><jats:italic>\/Fgf10<\/jats:italic><jats:sup>+\/+<\/jats:sup>) 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<jats:italic>in vitro<\/jats:italic>and restore branching to normal levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>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<jats:italic>Fgf10<\/jats:italic>and<jats:italic>Fgfr2b<\/jats:italic>null mice. Though we were able to rescue the abnormal phenotype associated with reduced<jats:italic>in vitro<\/jats:italic>FGF10\/FGFR2b signaling with exogenous FGF8 supplementation, our results indicate that the FGF10\/FGFR2b and FGF8\/FGFR2c are nonredundant signaling pathways essential for<jats:italic>in vivo<\/jats:italic>embryonic SMG development. What remains to be determined is the<jats:italic>in vivo<\/jats:italic>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.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1471-213x-5-11","type":"journal-article","created":{"date-parts":[[2005,6,22]],"date-time":"2005-06-22T18:34:44Z","timestamp":1119465284000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":117,"title":["FGF10\/FGFR2b signaling plays essential roles during in vivo embryonic submandibular salivary gland morphogenesis"],"prefix":"10.1186","volume":"5","author":[{"given":"Tina","family":"Jaskoll","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Abichaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Witcher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic G","family":"Sala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saverio","family":"Bellusci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad K","family":"Hajihosseini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Melnick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2005,6,22]]},"reference":[{"key":"62_CR1","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1002\/(SICI)1097-0185(19991101)256:3<252::AID-AR5>3.0.CO;2-6","volume":"256","author":"T Jaskoll","year":"1999","unstructured":"Jaskoll T, Melnick M: Submandibular gland morphogenesis: stage-specific expression of TGF-alpha, EGF, IGF, TGF-beta, TNF and IL-6 signal transduction in normal mice and the phenotypic effects of TGF-beta2, TGF-beta3, and EGF-R null mutations. 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