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Soluble dominant-negative receptor uncovers essential roles for fibroblast growth factors in multi-organ induction
G Celli1, W J LaRochelle, S Mackem
1Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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.
Insights
Fibroblast growth factor (FGF) signaling is crucial for organ development. A novel secreted FGF receptor mutant disrupted organogenesis, revealing FGF
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- Fibroblast growth factor (FGF) signaling is implicated in development, but its role in organogenesis is unclear due to genetic complexities.
- Individual gene knockouts often result in early lethality or functional redundancy, masking specific roles.
Purpose of the Study:
- To investigate the role of FGF signaling in vertebrate organogenesis using a novel dominant-negative approach.
- To determine the necessity of FGF signaling for the development of various organs and structures.
Main Methods:
- Generation of transgenic mice expressing a secreted, kinase-deficient fibroblast growth factor receptor (FGFR) mutant.
- Analysis of developmental defects and molecular markers in affected tissues.
- Comparison with transgenic mice expressing a membrane-tethered kinase-deficient FGFR.
Main Results:
- Secreted FGFR mutant expression led to agenesis or severe dysgenesis in kidneys, lungs, glands, and craniofacial and limb structures.
- The mutant disrupted early inductive signaling, confirming FGF's role in broad organ and limb development.
- Transgenic mice with membrane-tethered FGFR mutants were viable, highlighting the unique efficacy of secreted mutants.
Conclusions:
- Secreted dominant-negative FGFR mutants are effective tools for studying FGF signaling in vivo.
- FGF signaling is essential for the growth and patterning of a wide range of organs and limbs during vertebrate development.
- Endogenous soluble FGFR isoforms may regulate FGF activity during normal embryonic development.