Temporal–spatial ablation of neural crest in the mouse results in cardiovascular defects

Porras, Diego; Brown, Christopher B.

doi:10.1002/dvdy.21382

Cited by 50 publications

(43 citation statements)

References 46 publications

(52 reference statements)

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“…The left 6th PAA persists during fetal development and gives rise to the ductus arteriosus (Hutson and Kirby, 2007). By contrast, in animal models with cardiac NC deficiency, PAA regression occurs at random (Leatherbury et al, 1990;Nishibatake et al, 1987;Olaopa et al, 2011;Porras and Brown, 2008). This leads to variable aberrations in the final configuration of the AAAs, similar to the phenotypes observed in our mutants (Table S2, Fig.…”

Section: Ablation Of Fn1 In the Nc Results In Cardiovascular Abnormalsupporting

confidence: 80%

Neural crest cell-autonomous roles of fibronectin in cardiovascular development

Wang

Astrof

2015

Development

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The chemical and mechanical properties of extracellular matrices (ECMs) modulate diverse aspects of cellular fates; however, how regional heterogeneity in ECM composition regulates developmental programs is not well understood. We discovered that fibronectin 1 (Fn1) is expressed in strikingly non-uniform patterns during mouse development, suggesting that regionalized synthesis of the ECM plays cell-specific regulatory roles during embryogenesis. To test this hypothesis, we ablated Fn1 in the neural crest (NC), a population of multi-potent progenitors expressing high levels of Fn1. We found that Fn1 synthesized by the NC mediated morphogenesis of the aortic arch artery and differentiation of NC cells into vascular smooth muscle cells (VSMCs) by regulating Notch signaling. We show that NC Fn1 signals in an NC cell-autonomous manner through integrin α5β1 expressed by the NC, leading to activation of Notch and differentiation of VSMCs. Our data demonstrate an essential role of the localized synthesis of Fn1 in cardiovascular development and spatial regulation of Notch signaling.

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Section: Ablation Of Fn1 In the Nc Results In Cardiovascular Abnormalsupporting

confidence: 80%

Neural crest cell-autonomous roles of fibronectin in cardiovascular development

Wang

Astrof

2015

Development

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“…21,34,41). To assess cardiac function in the P0 mutants, we used noninvasive fetal ultrasound biomicroscopy-Doppler imaging.…”

Section: Ubm-doppler Imaging Analysis Reveals Abnormal Blood Flow In mentioning

confidence: 99%

“…Fate mapping analyses show that cNCC contribute to the aorticopulmonary septum (OFT septum), atrioventricular valves, semilunar valves, and conduction system in the mouse heart (2,18,32,38,40,48,53). Ablation experiments have demonstrated that cNCC are indispensable for OFT septation (14,41,54). Although cNCC are found in the semilunar valves of the pulmonary artery and the aorta, the precise function of cNCC in semilunar valve development is unknown.…”

mentioning

confidence: 99%

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

Nomura-Kitabayashi

Phoon

Kishigami

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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. Outflow tract cushions perform a critical valve-like function in the early embryonic heart requiring BMPRIA-mediated signaling in cardiac neural crest. Am J Physiol Heart Circ Physiol 297: H1617-H1628, 2009. First published August 28, 2009 doi:10.1152/ajpheart.00304.2009.-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 ϳE12.5, 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 BONE MORPHOGENETIC PROTEINS (BMPs), members of the TGF-␤ superfamily, transduce signals by binding to heteromeric type I and type II receptor complexes (23, 28). Among three type I receptors for BMPs, type IA receptor (BMPRIA, also known as ALK3) is highly expressed in the developing heart (7). Bmpr1a knockout mice die by embryonic day (E) 8.5 exhibiting failure in mesoderm formation (30). Mutations in genes encoding their ligands, Bmp2 or Bmp4, also cause early embryonic lethality (52, 55). Myocardial-or endocardial-specific disruptions of Bmpr1a result in defects of the endocardial cushions of the atrioventricular canal (AVC; Refs. 10, 33, 46) or malformation of the atrioventricular valves (11). Conditional disruption of Bmp2 or Bmp4 in the myocardium (19, 26) further suggests a role for BMP2 and BMP4 in regulating endocardial epithelialto-mesenchymal transformation (EMT) in the AVC. BMP signaling also pla...

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“…WNT signaling can operate through a JNK-dependent mechanism, which involves MEKK4 (Luo et al, 2003). Because the neural crest is an important contributor to the outflow tract (Jiang et al, 2000;Porras and Brown, 2008), it could be suggested that a proportion of MEKK4-deficient mice will likely have outflow tract malformations. In this regard, MEKK4 was recently shown to regulate developmental EMT in cardiac cushion tissue or the prevalvular regions of the embryonic heart.…”

Section: Mekk4 (Omim#*602425)mentioning

confidence: 99%