TY - JOUR T1 - Shp2 Knockdown and Noonan/LEOPARD Mutant Shp2–Induced Gastrulation Defects A1 - Jopling, Chris A1 - van Geemen, Daphne A1 - den Hertog, Jeroen Y1 - 2007/12/21 N2 -
Shp2 is a protein-tyrosine phosphatase and mutations in Shp2 cause the related Noonan and LEOPARD syndromes in humans. We used the zebrafish to investigate the cell biological role of Shp2 in early development. Shp2 knockdown and expression of mutant Shp2 that contained mutations corresponding to those found in human Noonan and LEOPARD patients, induced similar convergence and extension cell movement defects during gastrulation without affecting cell specification. Active Src family kinases and active RhoA rescued the Shp2 knockdown, indicating that signaling downstream of Shp2 was mediated by Src family kinases and RhoA. Expression of the Noonan and LEOPARD Shp2s in zebrafish induced craniofacial and cardiac defects that were reminiscent of the symptoms observed in human patients. Coinjections demonstrated that Noonan and LEOPARD Shp2s did not cooperate, which is consistent with the two mutants acting in the same signaling pathway with opposing effects. The finding that defective Shp2 signaling induced cell movement defects as early as gastrulation may have important implications for the monitoring and diagnosis of Noonan and LEOPARD syndromes in humans.