Fibroblast growth factor receptor-1 (FGFR-1) is essential for normal neural tube and limb development.
Fibroblast growth factor receptor-1 (FGFR-1) is a membrane-spanning tyrosine kinase that serves as a high-affinity receptor for fibroblast growth factors. It has recently been shown that FGFR-1 mutant embryos die during gastrulation displaying severe growth retardation and defective mesodermal structures. This early lethality has obscured functions of FGFR-1 that might occur later in development. To circumvent these embryonic defects, we generated chimeras by injecting FGFR-1-deficient (R1-/-) ES cells into wild-type blastocysts. We found that the fgfr-1 gene plays an important role after gastrulation and that it acts in a cell-autonomous fashion. Embryos with a high contribution of R1-/- cells replicate the FGFR-1 null phenotype and die during gastrulation. In contrast, the majority of embryos with a low contribution of R1-/- cells complete gastrulation and display malformations of posterior structures at later stages of embryogenesis. These abnormalities include truncation of embryonic structures, limb bud malformation, partial duplication of the neural tube, tail distortion, and spina bifida caused by the amplification of neural tissue in the posterior portion of the spinal cord. Thus, FGFR-1 plays a role in neurulation, suggesting that there may be a connection between FGFR-1-mediated signal pathways and neural tube defects, the most common malformations in the human central nervous system.
Deng
C
C
Laboratory of Biochemistry and Metabolism, National Institutes of Health, Bethesda, Maryland 20892, USA. ChuxiaD@BDG10.NIDDK.NIH.Gov
Bedford
M
M
Li
C
C
Xu
X
X
Yang
X
X
Dunmore
J
J
Leder
P
P
D000818:Animals; D002678:Chimera; D005121:Extremities / Q000196:embryology*; D005260:Female; D005838:Genotype; D008297:Male; D051379:Mice; D009420:Nervous System / Q000196:embryology*; D009436:Neural Tube Defects / Q000235:genetics; D010641:Phenotype; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000502:physiology*
D017468:Receptors, Fibroblast Growth Factor; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1