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

J Clin Invest. 2000 Aug;106(3):349-60. doi: 10.1172/JCI10272.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Cell Movement / physiology
  • DNA Primers / genetics
  • Epithelium / embryology
  • Epithelium / metabolism
  • Fetal Heart / embryology*
  • Fetal Heart / metabolism*
  • Gene Expression Regulation, Developmental
  • Glucuronosyltransferase / genetics
  • Glucuronosyltransferase / physiology*
  • Heart Defects, Congenital / enzymology
  • Heart Defects, Congenital / genetics
  • Hyaluronan Synthases
  • Hyaluronic Acid / metabolism*
  • In Situ Hybridization
  • Mesoderm / cytology
  • Mesoderm / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Electron, Scanning


  • DNA Primers
  • Hyaluronic Acid
  • Glucuronosyltransferase
  • Has2 protein, mouse
  • Hyaluronan Synthases