Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp-2

Abstract

Shp‐1, Shp‐2 and corkscrew comprise a small family of cytoplasmic tyrosine phosphatases that possess two tandem SH2 domains. To investigate the biological functions of Shp‐2, a targeted mutation has been introduced into the murine Shp‐2 gene, which results in an internal deletion of residues 46–110 in the N‐terminal SH2 domain. Shp‐2 is required for embryonic development, as mice homozygous for the mutant allele die in utero at mid‐gestation. The Shp‐2 mutant embryos fail to gastrulate properly as evidenced by defects in the node, notochord and posterior elongation. Biochemical analysis of mutant cells indicates that Shp‐2 can function as either a positive or negative regulator of MAP kinase activation, depending on the specific receptor pathway stimulated. In particular, Shp‐2 is required for full and sustained activation of the MAP kinase pathway following stimulation with fibroblast growth factor (FGF), raising the possibility that the phenotype of Shp‐2 mutant embryos results from a defect in FGF‐receptor signalling. Thus, Shp‐2 modulates tyrosine kinase signalling in vivo and is crucial for gastrulation during mammalian development.