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

Todd D. Camenisch, Andrew P. Spicer, Tammy Brehm-Gibson, Jennifer Biesterfeldt, Mary Lou Augustine, Anthony Calabro, Steven Kubalak, Scott E. Klewer, John A. McDonald

Research output: Contribution to journalArticlepeer-review

640 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)349-360
Number of pages12
JournalJournal of Clinical Investigation
Volume106
Issue number3
DOIs
StatePublished - 2000

ASJC Scopus subject areas

  • Medicine(all)

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