Soluble dominant-negative receptor uncovers essential roles for fibroblast growth factors in multi-organ induction and patterning
Open Access
- 16 March 1998
- journal article
- research article
- Published by Springer Nature in The EMBO Journal
- Vol. 17 (6) , 1642-1655
- https://doi.org/10.1093/emboj/17.6.1642
Abstract
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.Keywords
This publication has 82 references indexed in Scilit:
- Crossing receptor boundariesNature, 1996
- Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3Nature Genetics, 1996
- Roles for FGF8 in the Induction, Initiation, and Maintenance of Chick Limb DevelopmentCell, 1996
- Heparan Sulfates Mediate the Binding of Basic Fibroblast Growth Factor to a Specific Receptor on Neural Precursor CellsJournal of Biological Chemistry, 1995
- Craniofacial syndromes: no such thing as a single gene diseaseNature Genetics, 1995
- The ins and outs of fibroblast growth factorsCell, 1994
- TGFα overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreasCell, 1990
- Use of monospecific antisera and cRNA probes to localize the major changes in keratin expression during normal and abnormal epidermal differentiation.The Journal of cell biology, 1988
- Regulated expression of differentiation-associated keratins in cultured epidermal cells detected by monospecific antibodies to unique peptides of mouse epidermal keratinsDifferentiation, 1987
- The catalog of human cytokeratins: Patterns of expression in normal epithelia, tumors and cultured cellsPublished by Elsevier ,1982