The Role of Cell Autonomous Signaling by BMP in Endocardial Cushion Cells in AV Valvuloseptal Morphogenesis

Sugi, Yukiko; Zhou, Bin; Inai, Kei; Mishina, Yuji; Burnside, Jessica L.

doi:10.1007/978-4-431-54628-3_22

Cited by 2 publications

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“…al ., 2004) and BMP type I receptors, Bmpr1a and Acvr1 (Alk2) (Desgrosellier et al ., 2005; Inai et al., 2008; Wang et al ., 2005) are expressed in the AV endocardium and cushion mesenchyme at and after EMT stage. Based on the expression patterns of BMP ligands and their receptors, we hypothesized that autocrine BMP signaling within endocardium and progeny endocardial cushions regulates the maturation and remodeling of mesenchymalized AV cushions after-EMT (Sugi et al ., 2016). The Cre driver Nfatc1 Cre , which confers Cre-mediated recombination in endocardial cells and their progeny (Wu et al ., 2012), has enabled us to elucidate BMP signaling mechanisms in the endocardial lineage.…”

Section: Introductionmentioning

confidence: 99%

BMP2 expression in the endocardial lineage is required for AV endocardial cushion maturation and remodeling

Saxon

Baer

Barton

et al. 2017

Developmental Biology

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Distal outgrowth, maturation and remodeling of the endocardial cushion mesenchyme in the atrioventricular (AV) canal are the essential morphogenetic events during four-chambered heart formation. Mesenchymalized AV endocardial cushions give rise to the AV valves and the membranous ventricular septum (VS). Failure of these processes results in several human congenital heart defects. Despite this clinical relevance, the mechanisms governing how mesenchymalized AV endocardial cushions mature and remodel into the membranous VS and AV valves have only begun to be elucidated. The role of BMP signaling in the myocardial and secondary heart forming lineage has been well studied; however, little is known about the role of BMP2 expression in the endocardial lineage. To fill this knowledge gap, we generated Bmp2 endocardial lineage-specific conditional knockouts (referred to as Bmp2 cKOEndo) by crossing conditionally-targeted Bmp2flox/flox mice with a Cre-driver line, Nfatc1Cre, wherein Cre-mediated recombination was restricted to the endocardial cells and their mesenchymal progeny. Bmp2 cKOEndo mouse embryos did not exhibit failure or delay in the initial AV endocardial cushion formation at embryonic day (ED) 9.5–11.5; however, significant reductions in AV cushion size were detected in Bmp2 cKOEndo mouse embryos when compared to control embryos at ED13.5 and ED16.5. Moreover, deletion of Bmp2 from the endocardial lineage consistently resulted in membranous ventricular septal defects (VSDs), and mitral valve deficiencies, as evidenced by the absence of stratification of mitral valves at birth. Muscular VSDs were not found in Bmp2 cKOEndo mouse hearts. To understand the underlying morphogenetic mechanisms leading to a decrease in cushion size, cell proliferation and cell death were examined for AV endocardial cushions. Phospho-histone H3 analyses for cell proliferation and TUNEL assays for apoptotic cell death did not reveal significant differences between control and Bmp2 cKOEndo in AV endocardial cushions. However, mRNA expression of the extracellular matrix components, versican, Has2, collagen 9a1, and periostin was significantly reduced in Bmp2 cKOEndo AV cushions. Expression of transcription factors implicated in the cardiac valvulogenesis, Snail2, Twist1 and Sox9, was also significantly reduced in Bmp2 cKOEndo AV cushions. These data provide evidence that BMP2 expression in the endocardial lineage is essential for the distal outgrowth, maturation and remodeling of AV endocardial cushions into the normal membranous VS and the stratified AV valves.

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Section: Introductionmentioning

confidence: 99%

BMP2 expression in the endocardial lineage is required for AV endocardial cushion maturation and remodeling

Saxon

Baer

Barton

et al. 2017

Developmental Biology

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Heme oxygenase/carbon monoxide system and development of the heart

Mahan

2024

Medical Gas Research

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Progressive differentiation controlled by intercellular signaling between pharyngeal mesoderm, foregut endoderm, and neural crest-derived mesenchyme is required for normal embryonic and fetal development. Gasotransmitters (criteria: 1) a small gas molecule; 2) freely permeable across membranes; 3) endogenously and enzymatically produced and its production regulated; 4) well-defined and specific functions at physiologically relevant concentrations; 5) functions can be mimicked by exogenously applied counterpart; and 6) cellular effects may or may not be second messenger-mediated, but should have specific cellular and molecular targets) are integral to gametogenesis and subsequent embryogenesis, fetal development, and normal heart maturation. Important for in utero development, the heme oxygenase/carbon monoxide system is expressed during gametogenesis, by the placenta, during embryonic development, and by the fetus. Complex sequences of biochemical pathways result in the progressive maturation of the human heart in utero. The resulting myocardial architecture, consisting of working myocardium, coronary arteries and veins, epicardium, valves and cardiac skeleton, endocardial lining, and cardiac conduction system, determines function. Oxygen metabolism in normal and maldeveloping hearts, which develop under reduced and fluctuating oxygen concentrations, is poorly understood. “Normal” hypoxia is critical for heart formation, but “abnormal” hypoxia in utero affects cardiogenesis. The heme oxygenase/carbon monoxide system is important for in utero cardiac development, and other factors also result in alterations of the heme oxygenase/carbon monoxide system during in utero cardiac development. This review will address the role of the heme oxygenase/carbon monoxide system during cardiac development in embryo and fetal development.

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The Role of Cell Autonomous Signaling by BMP in Endocardial Cushion Cells in AV Valvuloseptal Morphogenesis

Cited by 2 publications

References 3 publications

BMP2 expression in the endocardial lineage is required for AV endocardial cushion maturation and remodeling

BMP2 expression in the endocardial lineage is required for AV endocardial cushion maturation and remodeling

Heme oxygenase/carbon monoxide system and development of the heart

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