Genetics & development of cardiac defect
Team Leader
S. ZAFFRAN
S. ZAFFRAN
Our work over the past few years has established the role of retinoic acid in defining the boundary of the heart fields during early development. Inhibition of retinoic acid signaling leads to expansion of cardiac progenitors. We have also shown 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 have recently demonstrated that Hoxb1 regulates proliferation and differentiation of second heart field progenitors and genetically interacts with Hoxa1 during cardiac outflow tract development. The role of retinoic acid signal and Hox genes in the patterning of the second heart field is being investigated.
Finally, elucidating the mechanisms involved in the restriction of cardiac progenitors will lead to a better understanding of CHDs and will ultimately lead to the development of novel therapies aimed at healing impaired human hearts.
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.
Congenital heart disease, defined as a gross structural abnormality of the heart, is the most common type of human birth defect, occurring in ∼9 per 1000 live births and at a significantly greater incidence in miscarriage and still births. The complexity in understanding the etiology of congenital heart diseases is heightened by disease variability influenced by genetic, epigenetic and/or environmental modifiers. Environmental factors are known to contribute to CHDs, but the pathophysiology and associated gene-environment interactions are not well-known. Well-recognized nongenetic causes of CHDs include environmental teratogens, such as excess maternal exposures to Vitamin A and its retinoid derivatives (e.g. isotretinoin). Pregestational maternal diabetes is a well-established adverse environment for embryonic development, due to fetal exposure to elevated blood glucose levels. It is associated with a 5X increase in CHD incidence. The molecular mechanisms underlying these lethal effects are not well understood. Dr Sonia Stefanovic is currently studying the consequence of deregulated Vitamin A signaling on mouse embryos genetically predisposed to heart defects and the impact of maternal diabetes on CHDs, projects being supported by H2020-MSCA-IF-2014 and ERA-CVD-2019.
Constitutional activation of molecular signaling pathways that transduce growth factor stimuli leads to both vascular and pigment cell anomalies. In humans, these take the form of a wide variety of congenital malformations and cancers. Our group studies how these pathways impact differentiation of a multipotent progenitor population known as neural crest cells (NCC).
We are exploring how a limited number of mutations in key molecules contribute to such diverse pathologies as common arterial trunk, giant congenital melanocytic nevus, cleft palate, microphthalmia, arteriovenous malformations in the skin and head, but also under other circumstances to melanoma and neuroblastoma. A whole-genome approach in families with giant congenital melanocytic nevus is enabling us to analyze inherited, non-coding modifier elements that may affect outcomes. Current projects are to characterize and identify the effects of signal modulation in our animal models and primary cell cultures from embryos and affected patients, with the goal of developing novel therapeutic approaches to treating or curing a wide class of individually often rare diseases and associations.
