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

• Published in: The Journal of clinical investigation Vol. 106; no. 3; pp. 349 - 360
• Main Authors: Camenisch, T D, Spicer, A P, Brehm-Gibson, T, Biesterfeldt, J, Augustine, M L, Calabro, Jr, A, Kubalak, S, Klewer, S E, McDonald, J A
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.08.2000
• Subjects: 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
• ISSN: 0021-9738
• 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.