Cardiac Outflow tract septation defects in a DiGeorge syndrome model respond to Minoxidil treatment
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE261206 | GEO | 2024/05/11
REPOSITORIES: GEO
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Project description:Cardiac Outflow tract septation defects in a DiGeorge syndrome model respond to Minoxidil treatment
| PRJNA1085754 | ENA
Project description:To examine a role for focal adhesion kinase (FAK) in cardiac morphogenesis, we generated a line of mice with a conditional deletion of FAK in nkx2-5-expressing cells (herein termed FAKnk mice). FAKnk mice died shortly after birth, likely resulting from a profound subaortic ventricular septal defect and associated malalignment of the outflow tract. Additional less penetrant phenotypes included persistent truncus arteriosus and thickened valve leaflets. Thus, conditional inactivation of FAK in nkx2-5-expressing cells leads to the most common congenital heart defect that is also a subset of abnormalities associated with tetralogy of Fallot and the DiGeorge syndrome. No significant differences in proliferation or apoptosis between control and FAKnk hearts were observed. However, decreased myocardialization was observed for the conal ridges of the proximal outflow tract in FAKnk hearts. Interestingly, chemotaxis was significantly attenuated in isolated FAK-null cardiomyocytes in comparison to genetic controls, and these effects were concomitant with reduced tyrosine phosphorylation of Crk-associated substrate (CAS). Thus, it is possible that ventricular septation and appropriate outflow tract alignment is dependent, at least in part, upon FAK-dependent CAS activation and subsequent induction of polarized myocyte movement into the conal ridges. Future studies will be necessary to determine the precise contributions of the additional nkx2-5-derived lineages to the phenotypes observed.
| S-EPMC1952084 | biostudies-literature
Project description:In vertebrate embryos, cardiac precursor cells of the primary heart field are specified in the lateral mesoderm. These cells converge at the ventral midline to form the linear heart tube, and give rise to the atria and the left ventricle. The right ventricle and the outflow tract are derived from an adjacent population of precursors known as the second heart field. In addition, the cardiac neural crest contributes cells to the septum of the outflow tract to separate the systemic and the pulmonary circulations. The amphibian heart has a single ventricle and an outflow tract with an incomplete spiral septum; however, it is unknown whether the cardiac neural crest is also involved in outflow tract septation, as in amniotes. Using a combination of tissue transplantations and molecular analyses in Xenopus we show that the amphibian outflow tract is derived from a second heart field equivalent to that described in birds and mammals. However, in contrast to what we see in amniotes, it is the second heart field and not the cardiac neural crest that forms the septum of the amphibian outflow tract. In Xenopus, cardiac neural crest cells remain confined to the aortic sac and arch arteries and never populate the outflow tract cushions. This significant difference suggests that cardiac neural crest cell migration into the cardiac cushions is an amniote-specific characteristic, presumably acquired to increase the mass of the outflow tract septum with the evolutionary need for a fully divided circulation.
| S-EPMC3082305 | biostudies-literature
Project description:In mammals, the outflow tract (OFT) of the developing heart septates into the base of the pulmonary artery and aorta to guide deoxygenated right ventricular blood into the lungs and oxygenated left ventricular blood into the systemic circulation. Accordingly, defective OFT septation is a life-threatening condition that can occur in both syndromic and nonsyndromic congenital heart disease. Even though studies of genetic mouse models have previously revealed a requirement for VEGF-A, the class 3 semaphorin SEMA3C, and their shared receptor neuropilin 1 (NRP1) in OFT development, the precise mechanism by which these proteins orchestrate OFT septation is not yet understood. Here, we have analyzed a complementary set of ligand-specific and tissue-specific mouse mutants to show that neural crest-derived SEMA3C activates NRP1 in the OFT endothelium. Explant assays combined with gene-expression studies and lineage tracing further demonstrated that this signaling pathway promotes an endothelial-to-mesenchymal transition that supplies cells to the endocardial cushions and repositions cardiac neural crest cells (NCCs) within the OFT, 2 processes that are essential for septal bridge formation. These findings elucidate a mechanism by which NCCs cooperate with endothelial cells in the developing OFT to enable the postnatal separation of the pulmonary and systemic circulation.
| S-EPMC4563681 | biostudies-literature
Project description:Evaluate the effect of the vB12 treatment on transcriptional profile of Tbx1 haploinsufficiency embryos we performed RNA-seq on whole E9.5 mouse embryos (21 somite stage) after treatment with vB12 (cyanocobalamin Sigma-Aldrich Prod. Number V2876) or vehicle (PBS) during pregnancy
2022-09-07 | GSE206737 | GEO
Project description:The Bmp4 signaling molecule is expressed in ventral splanchnic and branchial-arch mesoderm and outflow-tract (OFT) myocardium, suggesting a role for Bmp4 in OFT development. Inactivation of Bmp4 in the caudal branchial arch and splanchnic mesoderm and OFT myocardium by using a conditional null allele of Bmp4 and the Nkx2.5cre recombinase allele resulted in abnormal morphogenesis of branchial-arch arteries (BAAs) and defective OFT septation. Expression of aortic-sac myocardial markers was reduced and expression of the sm22LacZ transgene, a smooth-muscle marker, was attenuated in BAAs and conotruncus of Nkx2.5cre; Bmp4 conditional mutants. Moreover, we found tissue-specific functions for Bmp4 in the regulation of cellular proliferation and apoptosis. We also demonstrate a strong genetic interaction between Bmp4 and Bmp7 in OFT development. Our findings uncover a previously uncharacterized function for Bmp4 in vascular remodeling of the BAAs, and they show definitively that Bmp4, in cooperation with Bmp7, has a central role in OFT septation.
| S-EPMC384774 | biostudies-literature
Project description:MicroRNAs (miRNAs) have previously been implicated in a number of developmental processes, including development of the ventricular myocardium of the heart. To determine what, if any, additional roles miRNAs play in cardiogenesis, we deleted the miRNA-processing enzyme Dicer specifically in the developing murine heart. Embryos lacking cardiac Dicer lived longer than reported in previous studies using different alleles to remove cardiac Dicer activity and displayed a highly penetrant phenotype of double outlet right ventricle with a concurrent ventricular septal defect. Before the defect's onset, Pitx2c and Sema3c, both required for outflow tract morphogenesis, were up-regulated in Dicer-deficient hearts. Interestingly, mesenchymal apoptosis in the outflow tract normally required for outflow tract alignment was greatly decreased in the mutants, likely contributing directly to the observed phenotype. In sum, we demonstrate here a specific developmental process, that of outflow tract morphogenesis, being hindered by the deletion of miRNAs during cardiogenesis.
| S-EPMC2806718 | biostudies-other
Project description:In many experimental models and clinical examples, defects in the differentiation of the second heart field (SHF) and heart outflow tract septation defects are combined, although the mechanistic basis for this relationship has been unclear. We found that as the initial SHF population incorporates into the outflow tract, it is replenished from the surrounding progenitor territory. In retinoic acid (RA) receptor mutant mice, this latter process fails, and the outflow tract is shortened and misaligned as a result. As an additional consequence, the outflow tract is misspecified along its proximal-distal axis, which results in ectopic expression of TGFbeta2 and ectopic mesenchymal transformation of the endocardium. Reduction of TGFbeta2 gene dosage in the RA receptor-deficient background restores septation but does not rescue alignment defects, indicating that excess TGFbeta causes septation defects. This may be a common pathogenic pathway when second heart field and septation defects are coupled.
| S-EPMC2841063 | biostudies-literature
Project description:Hemizygous microdeletions on chromosome 22q11.2 cause a broad spectrum of congenital cardiovascular and craniofacial anomalies known collectively as DiGeorge Syndrome (DGS) that appear to arise from reduced expression of TBX1, a gene in the typically deleted region. Although mice lacking tbx1 display similar, yet more severe, cardiovascular and craniofacial defects, the mechanisms underlying these devastating phenotypes remain incompletely understood. Here, we report that Tbx1 is required prior to pharyngeal arch development to specify the nkx2.5+ cardiopharyngeal cell lineage that gives rise to the cardiovascular and crainiofacial structures absent in tbx1 null zebrafish. Importantly, the role of Tbx1 during cardiopharyngeal lineage specification is conserved in mammals. Further, we learned that DVR1, the zebrafish homolog of mammalian GDF1/3, functions downstream of Tbx1 for pharyngeal progenitor specification. Together, these studies unveil a new paradigm potentially underlying the cardiovascular and craniofacial defects observed in the DGS population.
2018-07-31 | GSE103120 | GEO
Project description:Smad ubiquitin regulatory factor 1 (SMURF1) is a HECT-type E3 ubiquitin ligase that plays a critical role in vertebrate development by regulating planar cell polarity (PCP) signaling and convergent extension (CE). Here we show that SMURF1 is involved in mammalian heart development. We find that SMURF1 is highly expressed in outflow tract cushion mesenchyme and Smurf1-/- mouse embryos show delayed outflow tract septation. SMURF1 is expressed in smooth muscle cells of the coronary arteries and great vessels. Thickness of the aortic smooth muscle cell layer is reduced in Smurf1-/- mouse embryos. We show that SMURF1 is a negative regulator of cardiomyogenesis and a positive regulator of smooth muscle cell and cardiac fibroblast differentiation, indicating that SMURF1 is important for cell-type specification during heart development. Finally, we provide evidence that SMURF1 localizes at the primary cilium where it may regulate bone morphogenetic protein (BMP) signaling, which controls the initial phase of cardiomyocyte differentiation. In summary, our results demonstrate that SMURF1 is a critical regulator of outflow tract septation and cell-type specification during heart development, and that these effects may in part be mediated via control of cilium-associated BMP signaling.
| S-EPMC6015040 | biostudies-literature