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This Article Full Text Full Text (PDF) Supplemental Videos All Versions of this Article: 297/5/H1617    most recent 00304.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Nomura-Kitabayashi, A. Articles by Mishina, Y. PubMed PubMed Citation Articles by Nomura-Kitabayashi, A. Articles by Mishina, Y.

Outflow tract cushions perform a critical valve-like function in the early embryonic heart requiring BMPRIA-mediated signaling in cardiac neural crest

¹Laboratory of Reproductive and Developmental Toxicology, National Institutes of Environmental Health Science, National Institutes of Health, Research Triangle Park, North Carolina; ²Pediatric Cardiology Program, New York University School of Medicine, New York, New York; ³Laboratory of Developmental Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethedsa, Maryland; ⁴Department of Developmental Genetics, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan; and ⁵Department of Biologic and Materials Science, University of Michigan School of Dentistry, Ann Arbor, Michigan

Submitted March 26, 2009 ; accepted in final form August 27, 2009

Neural crest-specific ablation of BMP type IA receptor (BMPRIA) causes embryonic lethality by embryonic day (E) 12.5, and this was previously postulated to arise from a myocardial defect related to signaling by a small population of cardiac neural crest cells (cNCC) in the epicardium. However, as BMP signaling via cNCC is also required for proper development of the outflow tract cushions, precursors to the semilunar valves, a plausible alternate or additional hypothesis is that heart failure may result from an outflow tract cushion defect. To investigate whether the outflow tract cushions may serve as dynamic valves in regulating hemodynamic function in the early embryo, in this study we used noninvasive ultrasound biomicroscopy-Doppler imaging to quantitatively assess hemodynamic function in mouse embryos with P0-Cre transgene mediated neural crest ablation of Bmpr1a (P0 mutants). Similar to previous studies, the neural crest-deleted Bmpr1a P0 mutants died at E12.5, exhibiting persistent truncus arteriosus, thinned myocardium, and congestive heart failure. Surprisingly, our ultrasound analyses showed normal contractile indices, heart rate, and atrioventricular conduction in the P0 mutants. However, reversed diastolic arterial blood flow was detected as early as E11.5, with cardiovascular insufficiency and death rapidly ensuing by E12.5. Quantitative computed tomography showed thinning of the outflow cushions, and this was associated with a marked reduction in cell proliferation. These results suggest BMP signaling to cNCC is required for growth of the outflow tract cushions. This study provides definitive evidence that the outflow cushions perform a valve-like function critical for survival of the early mouse embryo.

bone morphogenetic proteins; endocardial cushions; heart defects congenital; heart development; ultrasound biomicroscopy

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				D. Sedmera Pathways to embryonic heart failure Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1578 - H1579. [Full Text] [PDF]