Abstract 649: Dedicator of Cytokinesis 2 is Essential for the Initiation of Transforming Growth Factor-Beta-Induced Smooth Muscle Differentiation

Smooth muscle cell (SMC) differentiation is an important process during embryonic development. The underlying mechanisms regulating the SMC differentiation process, however, remain largely unknown. The present study identified dedicator of cytokinesis 2 (DOCK2) as one of the factors mediating the SMC differentiation. DOCK2 was important in mediating the transforming growth factor-β (TGF-β)-induced SMC differentiation from human embryonic stem cell derived mesenchymal cells (hES-MCs) and 10T 1/2 pluripotent embryonic mesenchymal cells. TGF-β induced DOCK2 expression during SMC differentiation as shown by the SMC marker expression including α-SMA, SM22α and calponin. DOCK2 overexpression induced while DOCK2 knockout inhibited SMC early marker gene expression. Mechanistically, DOCK2 induced SMC differentiation by activating phosphorylated p38 MAPK. DOCK2 overexpression induced while DOCK2 knockdown inhibited the level of phosphorylated p38. P38 pathway inhibitor dramatically decreased DOCK2-induced SMC marker gene expression. In vivo, reduced blood vessel formation was observed in the DOCK2-/- embryo yolk sac compared to the wild type yolk sac. Hemorrhage was also evident in the DOCK2-/- embryo. Histological analysis revealed defective expression of calponin and α-SMA in dorsal aorta of DOCK2-/- embryo. Taken together, our studies demonstrated that DOCK2 is an important novel factor regulating SMC differentiation.