Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme
Open accessAbstract
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.
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Mechanical signalling may play a role in the phenotypes observed in hyaluronan, FN1, and POSTN knockouts.
“Mechanical signalling may play a role in the phenotypes observed in the hyaluronan71, FN157, and POSTN72 knockouts, for which the latter is already known to mediate atrioventricular development through integrin signalling.”
From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [71]
The Targeted inactivation of the Has2 gene section reports compacted extracellular space and absent cardiac cushions in hyaluronan-deficient embryos. The discussion proposes HA-dependent receptor signalling in atrioventricular development, but does not identify mechanical signalling as a contributor to the knockout phenotype. This source supports the phenotype and a possible signalling role, not the mechanical qualifier; it does not address the FN1 or POSTN knockouts cited separately. (LLM, conf=0.78)
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Research works printed but not linked: 6
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“Mechanical signalling may play a role in the phenotypes observed in the hyaluronan 71 , FN1 57 , and POSTN 72 knockouts, for which the latter is already known to mediate atrioventricular development through integrin signalling.”
Background
- Authors
- Camenisch, T. D., Spicer, A. P., Brehm-Gibson, T., Biesterfeldt, J., Augustine, M. L., Calabro, A., Kubalak, S., Klewer, S. E., & McDonald, J. A.
- Affiliations
- Mayo Clinic (US)
- Cleveland Clinic (US)
- Medical University of South Carolina (US)
- University of Arizona (US)
- Corresponding author
- McDonald, John A.
- Venue
- Journal of Clinical Investigation
- Published
- 2000-08-01
- Volume
- 106
- Issue
- 3
- Pages
- 349-360
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC314332
- OpenAlex
- W2128466784
- Cited by
- 901
- References
- 0
- Citations by year
- 2026: 13 · 2025: 27 · 2024: 24 · 2023: 29 · 2022: 33 · 2021: 37 · 2020: 24 · 2019: 42 · 2018: 48 · 2017: 18 · 2016: 37 · 2015: 39 · 2014: 47 · 2013: 40 · 2012: 41
- FWCI
- 11.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- Mayo Foundation for Medical Education and Research
- Cleveland Clinic
- National Institutes of Health (5r01ar044689-04)
- National Heart, Lung, and Blood Institute (T32HL007897, T32 HL07897)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (1RO1 AR-44689)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- HAS2, hyaluronic acid, cardiac morphogenesis, epithelial-mesenchymal transition, Ras signaling, dominant negative Ras, cell migration, cell invasion, embryonic development, cardiac defects, vascular defects, gene targeting
- MeSH terms
- Hyaluronan Synthases, Animals, Base Sequence, Cell Movement, Epithelium, Fetal Heart, Heart Defects, Congenital, Hyaluronic Acid, Mesoderm, Mice, Inbred C57BL, Microscopy, Electron, Scanning, Glucuronosyltransferase, In Situ Hybridization, DNA Primers, Mice, Knockout, Gene Expression Regulation, Developmental, Mice
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