Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning
Open accessAbstract
Cardiac cushion development provides a valuable system to investigate epithelial to mesenchymal transition (EMT), a fundamental process in development and tumor progression. In the atrioventricular (AV) canal,endocardial cells lining the heart respond to a myocardial-derived signal,undergo EMT, and contribute to cushion mesenchyme. Here, we inactivated bone morphogenetic protein 2 (Bmp2) in the AV myocardium of mice. We show that Bmp2 has three functions in the AV canal: to enhance formation of the cardiac jelly, to induce endocardial EMT and to pattern the AV myocardium. Bmp2 is required for myocardial expression of Has2, a crucial component of the cardiac jelly matrix. During EMT,Bmp2 promotes expression of the basic helix-loop-helix factor Twist1,previously implicated in EMT in cancer metastases, and the homeobox genes Msx1 and Msx2. Deletion of the Bmp type 1A receptor, Bmpr1a, in endocardium also resulted in failed cushion formation,indicating that Bmp2 signals directly to cushion-forming endocardium to induce EMT. Lastly, we show that Bmp2 mutants failed to specify the AV myocardium with loss of Tbx2 expression uncovering a myocardial, planar signaling function for Bmp2. Our data indicate that Bmp2 has a crucial role in coordinating multiple aspects of AV canal morphogenesis.
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By E9.0, fluid shear stress from blood flow and signals from the myocardium including BMPs induce EndMT in a subset of endocardial cells lining the cushions.
“By E9.0, fluid shear stress from blood flow and signals from the myocardium, including BMPs, induce an endocardial-to-mesenchymal transition (EndMT) in a subset of endocardial cells lining the cushions9–13.”
From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [10]
The Introduction says a subset of endocardial cells undergoes EMT to form cushions, and the section ‘Bmp2 is a crucial inducer of EMT in the AV cushion’ reports that BMP signaling is required to induce it. Our copy does not establish that fluid shear stress induces this transition or that it occurs by E9.0; its E9.0 passage concerns myocardial Bmp2 expression. Page numbers are unavailable in the indexed copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn the Bmp2fl/fl;Nkx2-5-cre phenotype, AV cushions and mesenchyme are absent due to failure to initiate EndMT.
“This is in line with the Bmp2fl/fl;Nkx2-5-cre phenotype, where AV cushions and mesenchyme are absent due to the failure to initiate EndMT10,58.”
From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [10]
The section on embryonic lethality and AV cushion defects (page unavailable) reports that invasive mesenchyme failed to form because AV endocardial EMT was not induced. It describes severe AV cushion defects, not complete absence of the cushions; some mutant embryos retained cardiac jelly deposition. (LLM, conf=0.87)
Experimental — accuracy not yet measuredNicheNet analysis identifies activation of signalling pathways classically associated with EndMT initiation and mesenchymal development, including TGFβ superfamily, WNT, VEGF, and FGF signalling, signalling toward endocardial cells at E10.5.
“In our analysis, we see the activation of signalling pathways classically associated with EndMT initiation and mesenchymal development, including TGFβ superfamily9,10,67, WNT18, VEGF68,69, and FGF70 signalling.”
From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [10]
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- Authors
- Ma, L., Lu, M.-F., Schwartz, R. J., & Martin, J. F.
- Affiliations
- Texas A&M University System (US)
- Corresponding author
- Ma, Lijiang
- Martin, James F.
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2005-12-15
- Volume
- 132
- Issue
- 24
- Pages
- 5601-5611
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- OpenAlex
- W2085221145
- Cited by
- 525
- References
- 56
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 17 · 2023: 21 · 2022: 14 · 2021: 27 · 2020: 26 · 2019: 28 · 2018: 36 · 2017: 25 · 2016: 20 · 2015: 22 · 2014: 21 · 2013: 37 · 2012: 33
- FWCI
- 8.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Development (publishedVersion)
- PubMed (publishedVersion)
- OakTrust (Texas A&M University Libraries) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institute of Environmental Health Sciences (P30 ES9106-07, P30ES009106)
- National Institute of Dental and Craniofacial Research (R01DE013509, 2R01DE/HD12324-06)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- BMP-2, cardiac cushions, atrioventricular canal, epithelial-mesenchymal transition, endocardium, cardiac jelly, HAS2, TWIST1, MSX1, Msx2, BMPR1A, TBX2, heart development
- MeSH terms
- Hyaluronan Synthases, Animals, DNA-Binding Proteins, Endocardium, Epithelium, Heart, Mesoderm, Morphogenesis, Mutation, Nuclear Proteins, Glucuronosyltransferase, Signal Transduction, Transforming Growth Factor beta, Homeodomain Proteins, Bone Morphogenetic Proteins, Body Patterning, Mice, Twist-Related Protein 1, MSX1 Transcription Factor, Bone Morphogenetic Protein Receptors, Type I, Bone Morphogenetic Protein 2
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