ZAFFRAN Stéphane | Marseille Medical Genetics

Genetics of cardiac diseases

Congenital heart diseases are the most common type of birth defect, yet their causes often remain unknown.

Our laboratory investigates the molecular mechanisms underlying congenital heart disease (CHD). To achieve this, we employ a range of approaches, including experimental embryology, genetics, and transcriptomics.

Our primary objective is to elucidate the biological processes governing the development of the mouse and human hearts, with the ultimate goal of identifying and addressing the causes of cardiac diseases. We are particularly focused on the arterial and venous poles and valve development, as these regions are frequently implicated in CHD.

Our research centers on the molecular pathways that regulate cell fate decisions between distinct embryonic lineages, such as neural crest and mesoderm derivatives, during early heart development. In recent years, we have uncovered novel roles for several genes in cardiovascular development and identified candidate genes linked to less-studied CHD conditions, including bicuspid aortic valve and syndromic heart anomalies associated with rare malformation syndromes.

Cardiac progenitors

Over the past few years, our research has established the critical role of retinoic acid in defining the boundaries of heart fields during early development. We have demonstrated that inhibiting retinoic acid signaling leads to an expansion of cardiac progenitors. Additionally, we identified that anterior Hox genes, as downstream targets of retinoic acid, are expressed in distinct domains of the second heart field, contributing to the outflow tract and atria.

Using mutant mouse embryos, we recently showed that Hoxb1 regulates the proliferation and differentiation of second heart field progenitors and genetically interacts with Hoxa1 during the development of the cardiac outflow tract. Ongoing studies are investigating the role of retinoic acid signaling and Hox genes in the patterning of the second heart field, particularly within the pharyngeal region.

In collaboration with Fabienne Lescroart's team, we recently developed the gastruloid model, demonstrating its ability to recapitulate the earliest stages of cardiac and head muscle development using mouse embryonic stem cells.

Ultimately, uncovering the mechanisms that restrict cardiac progenitors will enhance our understanding of CHDs and pave the way for developing novel therapies to repair impaired human hearts.

Heart valve diseases

Anomalies of heart valves, including bicuspid aortic valve (BAV), are some of the commonest CHDs. Extracellular matrix changes occur in many valvular diseases. However, the molecular mechanisms leading to these pathologies are poorly understood. We have recently discovered the role of the zinc finger transcription factor Krox20 (Egr2) during heart valve development in mice. Loss of Krox20 function leads to defective aortic valve structure associated with aortic dysfunction. Functional promoter analysis demonstrated that Krox20 regulates the fibrilar collagens Col1a1 and Col3a1 genes during the remodeling of aortic valves. We continue our studies to uncover the contribution of different lineages in valve development and disease. We are now using state-of-the-art genetic technologies including next generation whole exome sequencing with the goal of discovering new genes in aortic valve disease such as BAV.

Team members

ZAFFRAN Stephane