Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme
| Autor: | Steven W. Kubalak, Todd D. Camenisch, Mary Lou Augustine, Scott E. Klewer, Tammy Brehm-Gibson, John A. McDonald, Anthony Calabro, Jennifer Biesterfeldt, Andrew P. Spicer |
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| Rok vydání: | 2000 |
| Předmět: |
Heart Defects
Congenital endocrine system Mesenchyme Hyaluronan Synthase 2 Epithelium Mesoderm Mice Endocardial cushion formation Fetal Heart Cell Movement medicine Animals Glucuronosyltransferase Hyaluronic Acid In Situ Hybridization HAS1 DNA Primers Mice Knockout biology Heart valve formation Base Sequence Gene targeting Gene Expression Regulation Developmental Cell migration General Medicine Molecular biology Mice Inbred C57BL Hyaluronan synthase medicine.anatomical_structure biology.protein Microscopy Electron Scanning Commentary Hyaluronan Synthases |
| Zdroj: | The Journal of clinical investigation. 106(3) |
| ISSN: | 0021-9738 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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