An essential role of Bmp4 in the atrioventricular septation of the mouse heart
Open accessAbstract
Proper septation and valvulogenesis during cardiogenesis depend on interactions between the myocardium and the endocardium. By combining use of a hypomorphic Bone morphogenetic protein 4 ( Bmp4 ) allele with conditional gene inactivation, we here identify Bmp4 as a signal from the myocardium directly mediating atrioventricular septation. Defects in this process cause one of the most common human congenital heart abnormalities, atrioventricular canal defect (AVCD). The spectrum of defects obtained through altering Bmp4 expression in the myocardium recapitulates the range of AVCDs diagnosed in patients, thus providing a useful genetic model with AVCD as the primary defect.
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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 [9]
The paper’s introductory discussion (page unavailable) says myocardial signals contribute to cushion formation and that TGF-β2 can activate EMT in explant assays. Its Results and Discussion detect Bmp4 near the forming cushion at E9.0, but find EMT proceeds when Bmp4 is deleted; other BMPs may compensate. The copy does not establish fluid shear stress as an inducer or the claimed combined mechanism by E9.0. (LLM, conf=0.88)
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 [9]
The paper identifies BMP4 as a TGFβ-superfamily signal required for atrioventricular septation after cushion formation (Results and Discussion; page unavailable). It also reports that TGFβ2 can activate EMT, but its own experiments find BMP4 dispensable for EMT initiation. The citing paper's NicheNet activation finding is its own analysis, not a finding attributed to this source. (LLM, conf=0.87)
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Research works printed but not linked: 2
- Gaussin, V., Van de Putte, T., Mishina, Y., Hanks, M.C., Zwijsen, A., Huylebroeck, D., Behringer, R.R., and Schneider, M.D. 2002. Endo- cardial cushion and myocardial defects after cardiac myocyte-specific conditional deletion of the bone morphogenetic protein receptor ALK3. Proc. Natl. Acad. Sci. 99: 2878-2883.
- Markwald, R.R. and Wessels, A. 2001. Overview of heart development. In Formation of the heart and its regulation (eds. R.J. Tomanek and R.B. Runyan), pp. 1-22. Birkhauser, Boston.
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“In our analysis, we see the activation of signalling pathways classically associated with EndMT initiation and mesenchymal development, including TGF β superfamily 9,10,67 , WNT 18 , VEGF 68,69 , and FGF 70 signalling.”
Method
- Authors
- Jiao, K., Kulessa, H., Tompkins, K., Zhou, Y., Batts, L., Baldwin, H. S., & Hogan, B. L. M.
- Affiliations
- Howard Hughes Medical Institute (US)
- Vanderbilt University Medical Center (US)
- Corresponding author
- Hogan, Brigid L.M.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2003-01-01
- Volume
- 17
- Issue
- 19
- Pages
- 2362-2367
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC218073
- OpenAlex
- W1979854824
- Cited by
- 366
- References
- 0
- Citations by year
- 2026: 13 · 2025: 10 · 2024: 14 · 2023: 11 · 2022: 13 · 2021: 17 · 2020: 22 · 2019: 23 · 2018: 17 · 2017: 13 · 2016: 20 · 2015: 15 · 2014: 16 · 2013: 14 · 2012: 23
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL-62177, P50HL062177)
- 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
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- BMP4, atrioventricular septal defect, heart development, congenital heart disease, mouse heart development, conditional gene inactivation, hypomorphic allele
- MeSH terms
- Animals, Animals, Newborn, Heart, Heart Defects, Congenital, Mice, Mutant Strains, Mice, Transgenic, Signal Transduction, Transforming Growth Factor beta, Gene Expression Regulation, Developmental, Bone Morphogenetic Proteins, Myocytes, Cardiac, Mice, Transforming Growth Factor beta2, Bone Morphogenetic Protein 4
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