SOLUBLE DOMINANT-NEGATIVE RECEPTOR UNCOVERS ESSENTIAL ROLES FOR FIBROBLAST GROWTH-FACTORS IN MULTIORGAN INDUCTION AND PATTERNING

Despite a wealth of experimental data implicating fibroblast growth fa ctor (FGF) signaling in various developmental processes, genetic inact ivation of individual genes encoding specific FGFs or their receptors (FGFRs) has generally failed to demonstrate their role in vertebrate o rganogenesis due to early embryonic lethality or functional redundancy . Here we show that broad mid-gestational expression of a novel secret ed kinase-deficient receptor, specific for a defined subset of the FGF superfamily, caused agenesis or severe dysgenesis of kidney, lung, sp ecific cutaneous structures, exocrine and endocrine glands, and cranio facial and limb abnormalities reminiscent of human skeletal disorders associated with FGFR mutations. Analysis of diagnostic molecular marke rs revealed that this soluble dominant-negative mutant disrupted early inductive signaling in affected tissues, indicating that FGF signalin g is required for growth and patterning in a broad array of organs and in limbs. In contrast, transgenic mice expressing a membrane-tethered kinase-deficient FGFR were viable. Our results demonstrate that secre ted FGFR mutants are uniquely effective as dominant-negative agents in vivo, and suggest that related soluble receptor isoforms expressed in wild-type mouse embryos may help regulate FGF activity during normal development.