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 ty rosine kinase that serves as a high-affinity receptor for fibroblast g rowth factors. It has recently been shown that FGER-1 mutant embryos d ie during gastrulation displaying severe growth retardation and defect ive 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 gastrulatio n. In contrast, the majority of embryos with a low contribution of R1( -/-) cells complete gastrulation and display malformations of posterio r structures at later stages of embryogenesis. These abnormalities inc lude truncation of embryonic structures, limb bud malformation, partia l duplication of the neural tube, tail distortion, and spina bifida ca used 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 pathway s and neural tube defects, the most common malformations in the human central nervous system. (C) 1987 Academic Press.