Soluble dominant-negative receptor uncovers essential roles for fibroblast growth factors in multi-organ induction and patterning.
Despite a wealth of experimental data implicating fibroblast growth factor (FGF) signaling in various developmental processes, genetic inactivation of individual genes encoding specific FGFs or their receptors (FGFRs) has generally failed to demonstrate their role in vertebrate organogenesis due to early embryonic lethality or functional redundancy. Here we show that broad mid-gestational expression of a novel secreted kinase-deficient receptor, specific for a defined subset of the FGF superfamily, caused agenesis or severe dysgenesis of kidney, lung, specific cutaneous structures, exocrine and endocrine glands, and craniofacial and limb abnormalities reminiscent of human skeletal disorders associated with FGFR mutations. Analysis of diagnostic molecular markers revealed that this soluble dominant-negative mutant disrupted early inductive signaling in affected tissues, indicating that FGF signaling 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 secreted 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.
Celli
G
G
Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
LaRochelle
W J
WJ
Mackem
S
S
Sharp
R
R
Merlino
G
G
D016475:3T3 Cells; D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D002460:Cell Line; D004627:Embryonic Induction / Q000502:physiology*; D005314:Embryonic and Fetal Development; D004817:Epidermis / Q000196:embryology; D005346:Fibroblast Growth Factors / Q000502:physiology*; D005799:Genes, Dominant; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D012995:Solubility; D019076:Transgenes
D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; D005346:Fibroblast Growth Factors; C496354:Fgfr2 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2