title: Outflow tract cushions perform a critical valve-like function in the early embryonic heart requiring BMPRIA-mediated signaling in cardiac neural crest.
abstract: 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 approximately 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.
authors.affiliation: Laboratory of Reproductive and Developmental Toxicology, National Institutes of Environmental Health Science, National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: Aya
authors.initials: A
authors.lastname: Nomura-Kitabayashi
authors.forename: Colin K L
authors.initials: CK
authors.lastname: Phoon
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kishigami
authors.forename: Julie
authors.initials: J
authors.lastname: Rosenthal
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Yamauchi
authors.forename: Kuniya
authors.initials: K
authors.lastname: Abe
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yamamura
authors.forename: Rajeev
authors.initials: R
authors.lastname: Samtani
authors.forename: Cecilia W
authors.initials: CW
authors.lastname: Lo
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000196:embryology / Q000378:metabolism / Q000503:physiopathology; D001158:Arteries / Q000196:embryology / Q000378:metabolism / Q000503:physiopathology; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002302:Cardiac Output; D002465:Cell Movement; D049109:Cell Proliferation; D020964:Embryo Loss; D005838:Genotype; D005865:Gestational Age; D006321:Heart / Q000196:embryology* / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000196:embryology / Q000378:metabolism* / Q000503:physiopathology; D006333:Heart Failure / Q000196:embryology / Q000378:metabolism* / Q000503:physiopathology; D006339:Heart Rate; D006351:Heart Valves / Q000196:embryology / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D033401:Microscopy, Acoustic; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009432:Neural Crest / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D012039:Regional Blood Flow; D015398:Signal Transduction; D014057:Tomography, X-Ray Computed; D014339:Truncus Arteriosus, Persistent / Q000196:embryology / Q000378:metabolism / Q000503:physiopathology; D018608:Ultrasonography, Doppler
chemical_list: D019485:Bone Morphogenetic Proteins; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I