Additive effects on craniofacial development upon conditional ablation of PDGFRα and SHP2 in the mouse neural crest...

Activity of the receptor tyrosine kinase PDGFRα and the tyrosine phosphatase SHP2 is critical for vertebrate craniofacial development. SHP2 has been shown to both positively and negatively regulate PDGFR signaling through the recruitment of Grb2 and dephosphorylation of the receptor, respectively. We sought to determine the effect of SHP2 binding to PDGFRα in the facial mesenchyme via phenotypic and biochemical analyses of an allelic series of mouse embryos with combined loss of both proteins in the neural crest lineage.

We demonstrated that SHP2 preferentially binds PDGFRα/α homodimers among the three PDGFR dimers. We showed that double-homozygous mutant embryos exhibit a combination, but not an improvement or worsening, of the phenotypes observed upon conditional ablation of PDGFRα or SHP2 in the neural crest lineage. We further revealed that cell death in the lateral nasal and maxillary processes underlies the upper jaw phenotypes in embryos with loss of SHP2. Finally, we showed that E10.5 Pdgfra^+/fl;Shp2^fl/fl;Wnt1-Cre^+/Tg embryos have increased phosphorylation of PDGFRα and the downstream effector Erk1/2 compared to control and double-heterozygous embryos.

We propose a putative model in which SHP2 binds and dephosphorylates PDGFRα while simultaneously increasing survival through an Erk1/2-independent mechanism.