Notch2 is required for the proliferation of cardiac neural crest-derived smooth muscle cells

Division of Cellular and Gene Therapies, Food and Drug Administration Bethesda, Maryland 20892, USA.
Developmental Dynamics (Impact Factor: 2.38). 04/2008; 237(4):1144-52. DOI: 10.1002/dvdy.21502
Source: PubMed


Mutations in Notch receptors and their ligands have been identified as the cause of human congenital heart diseases, indicating the importance of the Notch signaling pathway during heart development. In our study, we use Cre-Lox technology to inactivate Notch2 in several cardiac cell lineages to determine the functional requirements for Notch2 during mammalian heart development. Inactivation of Notch2 in cardiac neural crest cells resulted in abnormally narrow aortas and pulmonary arteries due to a decrease in smooth muscle tissue. The reduction in smooth muscle tissue was not due to cell migration defects but instead was found to be caused by less proliferation in smooth muscle cells during mid to late gestation. Our findings demonstrate that Notch2 is required cell autonomously for proper formation of the heart outflow tract and provides insights into the role of Notch2 in vascular smooth muscle development and the cardiovascular defects associated with Alagille syndrome.

Download full-text


Available from: Prajakta Varadkar, Apr 22, 2015
  • Source
    • "Notch signaling is associated with a wide range of developmental processes, including cell fate decisions in various cell types (Andersson et al, 2011). During embryonic cardiogenesis, Notch signaling affects both the SHF and the cNCCs, hence controlling right ventricle and outflow tract formation, vascular smooth muscle development, chamber specification, and trabeculation (McCright et al, 2001; High et al, 2007, 2008; Xin et al, 2007; Varadkar et al, 2008). SHF-specific deletion of Notch1 with an Isl1-Cre line promoted proliferation of Isl1 + progenitors and caused overexpression of b-catenin in the SHF, resulting in defects of the arterial pole including the right ventricle (Cohen et al, 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The latest discoveries and advanced knowledge in the fields of stem cell biology and developmental cardiology hold great promise for cardiac regenerative medicine, enabling researchers to design novel therapeutic tools and approaches to regenerate cardiac muscle for diseased hearts. However, progress in this arena has been hampered by a lack of reproducible and convincing evidence, which at best has yielded modest outcomes and is still far from clinical practice. To address current controversies and move cardiac regenerative therapeutics forward, it is crucial to gain a deeper understanding of the key cellular and molecular programs involved in human cardiogenesis and cardiac regeneration. In this review, we consider the fundamental principles that govern the "programming" and "reprogramming" of a human heart cell and discuss updated therapeutic strategies to regenerate a damaged heart. © 2015 The Authors.
    Full-text · Article · Feb 2015 · The EMBO Journal
  • Source
    • "The first CNV detected in our patient (1p12 deletion) results in a deletion of part of the NOTCH2 gene that can be mutated in Alagille syndrome, a multisystem disorder with predominantly liver-, skeletal, ophthalomologic and renal abnormalities [23]. We consider Alagille syndrome unlikely in our patient since she did not show any of these abnormalities, although highly variable expressivity of the affected systems has been described in subjects with NOTCH2 mutations [24]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Left ventricular hypertrabeculation/noncompaction (LVHT) is a cardiac abnormality of unknown etiology which has been described in children as well as in adults with and without chromosomal aberrations. LVHT has been reported in association with various cardiac and extracardiac abnormalities like epilepsy and facial dysmorphism. Case presentation A unique combination of LVHT, atrial septal defect, pulmonary valve stenosis, aortic stenosis, epilepsy and minor facial anomalies is presented in a 5.5 years old girl. Microarray-based genomic hybridization (array-CGH) detected six previously not described copy number variants (CNVs) inherited from a clinically unaffected father and minimally affected mother, thus, most likely, not clinically significant but rare benign variants. Conclusions Despite this complex phenotype de novo microdeletions or microduplications were not detected by array CGH. Further investigations, such as whole exome sequencing, could reveal point mutations and small indels as the possible cause.
    Full-text · Article · Jul 2012 · BMC Medical Genetics
  • Source
    • "We previously demonstrated that differentiation of vascular smooth muscle cells by endothelial cells was dependent upon NOTCH3 [14]. Notch2 is more widely expressed than Notch3, but is also present in vascular smooth muscle cells [11], [15], [16]. Two studies in particular have hinted at a role in smooth muscle cell regulation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Notch signaling has been implicated in the regulation of smooth muscle differentiation, but the precise role of Notch receptors is ill defined. Although Notch3 receptor expression is high in smooth muscle, Notch3 mutant mice are viable and display only mild defects in vascular patterning and smooth muscle differentiation. Notch2 is also expressed in smooth muscle and Notch2 mutant mice show cardiovascular abnormalities indicative of smooth muscle defects. Together, these findings infer that Notch2 and Notch3 act together to govern vascular development and smooth muscle differentiation. To address this hypothesis, we characterized the phenotype of mice with a combined deficiency in Notch2 and Notch3. Our results show that when Notch2 and Notch3 genes are simultaneously disrupted, mice die in utero at mid-gestation due to severe vascular abnormalities. Assembly of the vascular network occurs normally as assessed by Pecam1 expression, however smooth muscle cells surrounding the vessels are grossly deficient leading to vascular collapse. In vitro analysis show that both Notch2 and Notch3 robustly activate smooth muscle differentiation genes, and Notch3, but not Notch2 is a target of Notch signaling. These data highlight the combined actions of the Notch receptors in the regulation of vascular development, and suggest that while these receptors exhibit compensatory roles in smooth muscle, their functions are not entirely overlapping.
    Full-text · Article · May 2012 · PLoS ONE
Show more