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

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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
StatePublished - 2000

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Mesoderm
Hyaluronic Acid
Morphogenesis
Epithelium
Embryonic Development
Embryonic Structures
Gene Targeting
Cell Movement
Blood Vessels
hyaluronan synthase
Endothelial Cells
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Camenisch, T. D., Spicer, A. P., Brehm-Gibson, T., Biesterfeldt, J., Augustine, M. L., Calabro, A., ... McDonald, J. A. (2000). Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme. Journal of Clinical Investigation, 106(3), 349-360.

Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme. / Camenisch, Todd D; Spicer, Andrew P.; Brehm-Gibson, Tammy; Biesterfeldt, Jennifer; Augustine, Mary Lou; Calabro, Anthony; Kubalak, Steven; Klewer, Scott E; McDonald, John A.

In: Journal of Clinical Investigation, Vol. 106, No. 3, 2000, p. 349-360.

Research output: Contribution to journalArticle

Camenisch, TD, Spicer, AP, Brehm-Gibson, T, Biesterfeldt, J, Augustine, ML, Calabro, A, Kubalak, S, Klewer, SE & McDonald, JA 2000, 'Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme', Journal of Clinical Investigation, vol. 106, no. 3, pp. 349-360.
Camenisch, Todd D ; Spicer, Andrew P. ; Brehm-Gibson, Tammy ; Biesterfeldt, Jennifer ; Augustine, Mary Lou ; Calabro, Anthony ; Kubalak, Steven ; Klewer, Scott E ; McDonald, John A. / Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme. In: Journal of Clinical Investigation. 2000 ; Vol. 106, No. 3. pp. 349-360.
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