FGFRs constitute a family of four membrane-spanning tyrosine kinases (FGFR1-4) which serve as high affinity receptors for at least nine growth factors (FGF1-9). 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. Analyses of the mutant mice indicated that the FGF receptors mediated signals may have many important biological functions, including embryonic growth, developmental induction and differentiation, mesoderm patterning, cell proliferation, organ formation, as well as bone growth and development. We show that FGFR-1 is a major receptor for FGF signals during embryonic development. FGFR-1 null embryos were developmentally retarded and die prior to or during gastrulation with multiple defects in the axial and paraxial mesoderm. Using chimerical animal formation and isoform knockouts approaches, we demonstrated that this gene also plays an essential role at post gastrulation process. FGFR-1 null embryos were normal during gastrulation, however, displayed abnormalities in chorioallantoic fusion, placental formation and limb bud initiation. Our data also indicated that FGFR-3 and FGFR-4 signals, function cooperatively in the development and homeostasis of multiple organ systems. Recently, it was demonstrated that alterations in FGFR-1, FGFR-2 and FGFR-3 are responsible for at least seven dominant heritable human skeletal dysmorphologies that include Pfeiffer syndrome (PS), Crouzon syndrome (CS), Jackson-Weiss syndrome (JS), Apert syndrome (AS), achondroplasia (ACH), thanatophoric dysplasia (TD) and hypochondroplasia (HCH). All of these diseases are cause by single amino acid mutations and exhibit extensive craniofacial, axial and/or appendicular bone abnormalities. Our preliminary study suggested that these diseases appear unlikely to be a consequence of haploinsufficiency or loss-of-function of FGF receptors. Rather, they may result from a grades ligand-independent activation of the receptors.
