Studies have been carried out on functions of fibroblast growth factor receptors (FGFRs) in mammalian development. FGFRs constitute a family of four membrane-spanning tyrosine kinases (FGFR1-4) which serve as high affinity receptors for at least fourteen growth factors (FGF1-14). To study functions of FGF/FGFR signals in development, mice have been created that carry targeted disruption of each individual receptor through homologous recombination in ES cells. We have previously shown that FGFR1 is essential for embryonic growth and mesoderm patterning during gastrulation. Analyzing chimeric animals, we demonstrated that this gene plays multiple functions at post gastrulation process, including neural tube development and limb mesenchymal cell proliferation. We now show that the long isoform of FGFR1, which contains three Ig loops, plays a critical role in node posterior migration. Mice carrying a targeted disruption this isoform displayed multiple abnormalities in the posterior embryonic structures and die at E9.5-11.5 due to a failure in establishing embryonic circulation. Analyses of mice deficient for other FGFRs indicated that FGFR2 signals are essential for a reciprocal regulation loop between FGF8 and FGF10 during limb induction. We also show that FGFR3 is a negative regulator in bone growth, and FGFR3 and FGFR4 signals function cooperatively in the development and homeostasis of multiple organ systems. Animals lacking Fgfr4 are phenotypically normal whereas those deficient for both FGFR3 and FGFR4 often exhibit breathing difficulties. There appears to be no perturbation in the early phases of branching morphogenesis, as the lungs of newborn double mutants are normal in appearance. However, 5-10 days after birth, lungs of FGFR3 and FGFR4 double homzygous mice fail to undergo secondary septation and consequently do not form alveoli. This data indicates that FGFR3 and FGFR4 signals work synergistically in controlling the alveolarization during postnatal lung development. Experiments is also being carried out to study functions of several tumor suppressor genes including Brca1, Smad2, Smad3, Smad4 and Smad5. Mutations have been introduced into these genes through homologous recombination in ES cells. We are now carrying out phenotypeic analyses of these mutant mice to uncover the functions of these genes.
