Journal of Clinical Investigation · 2000 · 897 citations · 67 references
Life SciencesDevelopmental BiologyMolecular BiologyEmbryogenesisMorphogenesisSignal TransductionAngiogenesisCardiovascular DevelopmentEpithelial-mesenchymal InteractionsEpithelial-to-mesenchymal TransitionExtracellular MatrixHeart DevelopmentAberrant Ras ActivationEmbryonic Development GeneticsEpithelial-mesenchymal TransformationHyaluronan BiologyHyaluronan SignalingRas Pathway ActivationRas SignalingRas Signaling Activation
The study aimed to identify hyaluronan synthase‑2 as the source of hyaluronan during embryogenesis and to investigate its in vivo function via gene targeting. The authors generated Has2 knockout embryos by gene targeting and examined the resulting phenotypes. Has2‑deficient embryos lack hyaluronan, exhibit fatal cardiac and vascular abnormalities, and their hearts fail to undergo endothelial‑to‑mesenchyme transition—a defect that can be mimicked by dominant‑negative Ras, rescued by exogenous HA or activated Ras, highlighting HA’s essential role and revealing a novel HA‑Ras–dependent migration pathway.
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.
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