Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesisand hyaluronan-mediated transformation of epithelium to mesenchyme

We identified hyaluronan synthase-2 (Has2) as a likely source of hyaluronan (HA) during embryonic development, and we used gene targeting to study its function in vivo. Has2(-/-) embryos lack HA, exhibit severe cardiac and va scular abnormalities, and die during midgestation (E9.5-10), Heart explants from Has2(-/-) embryos lack the characteristic transformation of cardiac e ndothelial cells into mesenchyme, an essential developmental event that dep ends on receptor-mediated intracellular signaling, This defect is reproduce d by expression of a dominant-negative Ras in wild-type heart explants, and is reversed in Has2(-/-) explants by gene rescue, by administering exogeno us HA, or by expressing activated Ras. Conversely, transformation in Has2(- /-) explants mediated by exogenous HA is inhibited by dominant-negative Ras , Collectively, our results demonstrate the importance of HA in mammalian e mbryogenesis and the pivotal role of Has2 during mammalian development. The y also reveal a previously unrecognized pathway for cell migration and inva sion that is HA-dependent and involves Ras activation.