Participants

José Luis de la Pompa and collaborators José Luis de la Pompa Centro Nacional de Investigaciones Cardiovasculares. CNIC Departamento de Biologia del Desarrollo Cardiovascular

Intercelular Signaling in Cardiovascular Development and Homeostasis

The Notch signaling pathway is an ancient local cell-to-cell signaling mechanism that regulates embryonic cell fate determination, differentiation and patterning. Specific Notch ligands, receptors and targets are expressed in the heart from early developmental stages and during adult life, and little is known about their role in cardiac development and physiology.

Notch in cardiac valve development and disease

Our previous work has shown that during cardiac valve development, Notch is required for endocardial differentiation and formation of the cardiac valve primordia. In the embryo, Notch1 activity is detected in the endocardium overlying the presumptive valve territory. Molecular and biochemical analysis shows that in the normal embryo Notch induces endocardial expression of the transcriptional represor Snail that in turn, represses VE-cadherin expression, allowing the epithelial-to-mesenchyme transformation (EMT) that leads to formation of the valvular primordium. Abrogation of Notch signaling in mice or zebrafish causes a block in EMT [†immerman et al., 2004]. Our recent gain-of-function studies in mice indicate that Notch may confer chamber identity as ectopic Notch activation leads to EMT in the ventricles.

The human NOTCH1 gene is mutated in families with an autosomal-dominant inheritance of congenital heart disease, which consisted predominantly in bicuspid aortic valve and valve calcification. Genomic analysis of these families indicated that the congenital heart disease phenotype was linked to a region that contained the NOTCH1 gene. Sequencing of the full NOTCH1 gene revealed a premature stop codon. These NOTCH1 mutations generate truncated and unstable transcripts and provide compelling genetic evidence that NOTCH1 haplo-insufficiency results in human congenital heart disease [Garg et al., (2005) Nature 437, 270]. We want to combine mouse models and genomic sequencing analysis in humans to determine the impact of alterations in Notch signaling in valve maintenance and human cardiac valve disease.

Notch in ventricular chamber development and adult heart homeostasis

Notch regulates cardiomyocyte proliferation and differentiation during ventricular development [Grego-Bessa et al., 2007] and alterations in Notch signaling may be involved in some forms of human cardimyopathies. Different Notch genes are expressed in the adult heart and we are currently investigating the implication of Notch in different pathological proceses such as cardiac hyperthrophy and in cardiac progenitor cells physiology.

Relevance

- Social Impact: 750.000 newborns/year show congenital heart disease (VSD), and very little is known about the disease ethiology and molecular basis,

- Non-lethal forms of CHD may affect heart function and quality of life in the adult (aortic valve degeneration/NOTCH1),

- CDV disease (Coronaries, myocardial infarction, etc) has surpassed cancer as the main cause of death in Western countries: Understanding the basic molecular mechanisms underlying cardiac repair (progenitor pool maintenance and mobilization, etc) will contribute to the design of therapeutic strategies to treat cardiac degeneration and failure.

Publications

Links

  • Heartrepair

    Heartrepair is an european research consortium aiming at investigating the genomics of cardiac development and repair, leading to an improved understanding of the pathophysiology of heart disease and advance the development of cellular replacement.

  • Web page
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