Gene expression profiles of mouse submandibular gland development: FGFR1 regulates branching morphogenesis in vitro through BMP- and FGF- dependent mechanisms
2002
Analyses of gene expression profiles at five different stages of mouse
submandibular salivary gland development provide insight into gland
organogenesis and identify genes that may be critical at different stages.
Genes with similar expression profiles were clustered, and RT-PCR was used to
confirm the developmental changes. We focused on fibroblast growth factor
receptor 1 (FGFR1), as its expression is highest early in gland development.
We extended our array results and analyzed the developmental expression
patterns of other FGFR and FGF isoforms. The functional significance of FGFR1
was confirmed by submandibular gland organ culture. Antisense oligonucleotides
decreased expression of FGFR1 and reduced branching morphogenesis of the
glands. Inhibiting FGFR1 signaling with SU5402, a FGFR1 tyrosine kinase
inhibitor, reduced branching morphogenesis. SU5402 treatment decreased cell
proliferation but did not increase apoptosis. Fgfr, Fgf and
Bmp gene expression was localized to either the mesenchyme or the
epithelium by PCR, and then measured over time by real time PCR after SU5402
treatment. FGFR1 signaling regulates Fgfr1, Fgf1, Fgf3 and
Bmp7 expression and indirectly regulates Fgf7, Fgf10 and
Bmp4 . Exogenous FGFs and BMPs added to glands in culture reveal
distinct effects on gland morphology. Glands cultured with SU5402 were then
rescued with exogenous BMP7, FGF7 or FGF10. Taken together, our results
suggest specific FGFs and BMPs play reciprocal roles in regulating branching
morphogenesis and FGFR1 signaling plays a central role by regulating both FGF
and BMP expression.
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