Murine Fibroblast Growth Factor Receptor 1alpha Isoforms Mediate Node Regression and Are Essential for Posterior Mesoderm Development

Dev Biol. 1999 Apr 15;208(2):293-306. doi: 10.1006/dbio.1999.9227.

Abstract

Alternative splicing in the fibroblast growth factor receptor 1 (Fgfr1) locus generates a variety of splicing isoforms, including FGFR1alpha isoforms, which contain three immunoglobulin-like loops in the extracellular domain of the receptor. It has been previously shown that embryos carrying targeted disruptions of all major isoforms die during gastrulation, displaying severe growth retardation and defective mesodermal structures. Here we selectively disrupted the FGFR1alpha isoforms and found that they play an essential role in posterior mesoderm formation during gastrulation. We show that the mutant embryos lack caudal somites, develop spina bifida, and die at 9.5-12.5 days of embryonic development because they are unable to establish embryonic circulation. The primary defect is a failure of axial mesoderm cell migration toward the posterior portions of the embryos during gastrulation, as revealed by regional marker analysis and DiI labeling. In contrast, the anterior migration of the notochord is unaffected and the embryonic structures rostral to the forelimb are relatively normal. These data demonstrate that FGF/FGFR1alpha signals are posteriorizing factors that control node regression and posterior embryonic development.

MeSH terms

  • Abnormalities, Multiple
  • Animals
  • Brain / abnormalities
  • Cell Communication
  • Cell Movement*
  • Crosses, Genetic
  • Embryo, Mammalian / pathology
  • Gastrula
  • Genes, Lethal
  • Genotype
  • Mesoderm / cytology*
  • Mice
  • Mice, Mutant Strains / embryology*
  • Mutagenesis, Site-Directed
  • Mutation
  • Protein Isoforms / deficiency
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Receptor Protein-Tyrosine Kinases / deficiency
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptors, Fibroblast Growth Factor / deficiency
  • Receptors, Fibroblast Growth Factor / genetics*
  • Receptors, Fibroblast Growth Factor / metabolism
  • Somites
  • Spinal Dysraphism / etiology
  • Spinal Dysraphism / genetics

Substances

  • Protein Isoforms
  • Receptors, Fibroblast Growth Factor
  • Fgfr1 protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 1