Abstract 1472: SHP2 Deletion in Pre-Migratory Neural Crest Cells Phenocopies Aspects of the 22q11 Deletion Syndrome via the ERK1/2 Pathway
PTPN11, located on chromosome 12q24.1, encodes the protein tyrosine phosphatase SHP2, which is essential for gastrulation of vertebrate embryos. Neural crest cells (NCCs) are often referred to as the fourth germ layer as they give rise to many diverse cell types, processes and organs, some of which are involved in craniofacial and cardiovascular formation. To examine the role of SHP2 in NCC function, we generated NCC conditional SHP2 knockout mice using the Wnt1-Cre/loxP system. NCC conditional SHP2 knockout embryos showed cardiovascular defects including persistent truncus arteriosus, semilunar valve dysplasia, and ventricular septal defects, as well as thymic, parathyroid and craniofacial anomalies, leading to perinatal lethality. NCCs in which SHP2 was ablated appeared to cycle normally. Normal numbers of NCCs were maintained throughout embryogenesis and initial migration of NCC to the face and the pharyngeal arch region also appeared to be normal. However, cardiac NCCs failed to migrate to the proximal outflow tract, cushions and epicardium and did not differentiate into vascular smooth muscle and cardiac ganglia, while the cranial NCCs failed to differentiate into cartilage and bone. Many of these malformations appeared to phenocopy the 22q11 deletion syndrome. While SHP2 potentiates signaling through the MAP-kinase pathway and ERK1/2 is transiently activated in the NCCs during normal embryogenesis, ERK1/2 is down-regulated in the mutant NCCs. Strikingly, ERK1/2 down-regulation is also found in FGF8 and Crkl deficient mice, which also phenocopy the 22q11 deletion syndrome. Taken together, our data show that SHP2 is necessary for the differentiation of NCCs into diverse cell lineages and provide mechanistic insight into the role ERK1/2 activity in NCCs plays in phenocopying the 22q11 deletion syndrome.