Wnt signaling in heart valve development and osteogenic gene induction
Open accessAbstract
Wnt signaling mediated by beta-catenin has been implicated in early endocardial cushion development, but its roles in later stages of heart valve maturation and homeostasis have not been identified. Multiple Wnt ligands and pathway genes are differentially expressed during heart valve development. At E12.5, Wnt2 is expressed in cushion mesenchyme, whereas Wnt4 and Wnt9b are predominant in overlying endothelial cells. At E17.5, both Wnt3a and Wnt7b are expressed in the remodeling atrioventricular (AV) and semilunar valves. In addition, the TOPGAL Wnt reporter transgene is active throughout the developing AV and semilunar valves at E16.5, with more localized expression in the stratified valve leaflets after birth. In chicken embryo aortic valves, genes characteristic of osteogenic cell lineages including periostin, osteonectin, and Id2 are expressed specifically in the collagen-rich fibrosa layer at E14. Treatment of E14 aortic valve interstitial cells (VICs) in culture with osteogenic media results in increased expression of multiple genes associated with bone formation. Treatment of VIC with Wnt3a leads to nuclear localization of beta-catenin and induction of periostin and matrix gla protein but does not induce genes associated with later stages of osteogenesis. Together, these studies provide evidence for Wnt signaling as a regulator of endocardial cushion maturation as well as valve leaflet stratification, homeostasis, and pathogenesis.
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Candidate signals from the endocardium, like TGFβ1 and WNT ligands, are identified as known mediators of valve mesenchymal proliferation.
“We identify candidate signals from the endocardium, like TGFβ1 and WNT ligands, which are known mediators of valve mesenchymal proliferation46,75.”
From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [46]
The Discussion reports that Wnt signaling promotes mesenchymal cell proliferation in atrioventricular cushions, and the Results identify Wnt4 and Wnt9b in the endocardial endothelial cells overlying those cushions. But the Discussion says the roles of those endocardial ligands are unknown, and the cited passages do not establish TGFβ1 as a mediator. No page numbers are available in our copy. (LLM, conf=0.84)
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“We identify candidate signals from the endocardium, like TGF β 1 and WNT ligands, which are known mediators of valve mesenchymal proliferation 46,75 .”
BackgroundNahia, K. A., Migdał, M., Quinn, T. A., Poon, K., Łapiński, M., Sulej, A., Liu, J., Mondal, S. S., Pawlak, M., Bugajski, Ł., et al. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03939-y · Cited by 13 · see citing works
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Molecular Mechanisms of Heart Valve Development and Disease
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- Authors
- Alfieri, C. M., Cheek, J., Chakraborty, S., & Yutzey, K. E.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Yutzey, Katherine E.
- Venue
- Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2010-02
- Volume
- 338
- Issue
- 2
- Pages
- 127-135
- ISSN
- 0012-1606 (ISSN-L)
- PMC
- PMC2814915
- OpenAlex
- W1968858235
- Cited by
- 138
- References
- 70
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 11 · 2021: 4 · 2020: 9 · 2019: 10 · 2018: 10 · 2017: 10 · 2016: 18 · 2015: 9 · 2014: 12 · 2013: 7 · 2012: 7
- FWCI
- 2.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1262 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Developmental Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01 HL094319, R01 HL082716)
- American Heart Association–Great Rivers Affiliate (0825627D)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Wnt signaling, heart valve development, endocardial cushion, β-catenin, Wnt3a, Wnt2, Wnt4, Wnt9b, Wnt7b, periostin, SPARC, Id2, matrix Gla protein, valvular interstitial cells, aortic valve, chick embryo
- MeSH terms
- Animals, Aortic Valve, Chick Embryo, Embryo, Mammalian, Heart Valves, Osteogenesis, Proto-Oncogene Proteins, Signal Transduction, Gene Expression Regulation, Developmental, Wnt Proteins, Mice, Wnt3 Protein, Wnt3A Protein
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