[HTML][HTML] Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme

TD Camenisch, AP Spicer… - The Journal of …, 2000 - Am Soc Clin Investig
TD Camenisch, AP Spicer, T Brehm-Gibson, J Biesterfeldt, ML Augustine, A Calabro…
The Journal of clinical investigation, 2000Am Soc Clin Investig
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 vascular abnormalities, and die during
midgestation (E9. 5–10). Heart explants from Has2–/–embryos lack the characteristic
transformation of cardiac endothelial cells into mesenchyme, an essential developmental
event that depends on receptor-mediated intracellular signaling. This defect is reproduced …
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 vascular abnormalities, and die during midgestation (E9.5–10). Heart explants from Has2–/– embryos lack the characteristic transformation of cardiac endothelial cells into mesenchyme, an essential developmental event that depends on receptor-mediated intracellular signaling. This defect is reproduced by expression of a dominant-negative Ras in wild-type heart explants, and is reversed in Has2–/– explants by gene rescue, by administering exogenous 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 embryogenesis and the pivotal role of Has2 during mammalian development. They also reveal a previously unrecognized pathway for cell migration and invasion that is HA-dependent and involves Ras activation.
The Journal of Clinical Investigation