Congenital heart defects are the most common class of birth defect, however, their cause is often unknown.

Our laboratory is interested in the molecular and cellular mechanisms of heart development and disease. We use experimental embryological, genetic and molecular approaches to analyze the development of the cardiovascular system.

Our goals are to better understand the biological steps in the embryonic development of mouse and human cardiovascular systems in order to identify and treat the causes of such diseases. We are specifically interested in arterial and venous poles as well as valve development, as they are affected in the majority of congenital heart defects.

Our research focuses on the molecular programs controlling cell fate decisions between distinct embryonic cell lineages, derivatives of the neural crest and mesoderm, in the early forming heart tube and blood vessels. Our work over the past few years has established a novel role for a number of genes during cardiovascular development and identified several candidate genes for less-studied congenital heart defects, such as bicuspid aortic valve or syndromic heart anomalies in rare malformation syndromes.

Our work over the past few years has established the role of the 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, we think that 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 injured 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 uncovered the role of the zinc finger transcription factor Krox20 during heart valve development. 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 to discovering new genes for aortic valve disease such as BAV.

Group leader: Heather Etchevers

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.


Stefanovic, S.  et al. 2017

Mechanisms of retinoic acid signaling during cardiogenesis

Substantial experimental and epidemiological data have highlighted the interplay between nutritional and genetic factors in the development of congenital heart defects. Retinoic acid (RA), a...
Mech. Dev. - issue: - volume: 143 - pages: 9-19.

Roux, M.  et al. 2017

Hoxa1 and Hoxb1 are required for pharyngeal arch artery development

Hox transcription factors play critical roles during early vertebrate development. Previous studies have revealed an overlapping function of Hoxa1 and Hoxb1 during specification of the rhombomeres...
Mech. Dev. - issue: - volume: 143 - pages: 1-8.

Theron, A.  et al. 2016

An uncommon cause of tricuspid regurgitation: three-dimensional echocardiographic incremental value, surgical and genetic insights

Congenital tricuspid valve disease is a rare defect that includes regurgitation, stenosis and Ebstein's anomaly. We report a case of severe tricuspid regurgitation associated with functional mitral...
Eur. J. Cardio-Thorac. Surg. - issue: 1 - volume: 50 - pages: 180-182.

Roux, M.  et al. 2016

Hox Genes in Cardiovascular Development and Diseases

Congenital heart defects (CHD) are the leading cause of death in the first year of life. Over the past 20 years, much effort has been focused on unraveling the genetic bases of CHD. In particular,...
J. Dev. Biol. - issue: 2 - volume: 4 - pages: 14.

Chassaing, N.  et al. 2016

Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network

Ocular developmental anomalies (ODA) such as anophthalmia/microphthalmia (AM) or anterior segment dysgenesis (ASD) have an estimated combined prevalence of 3.7 in 10,000 births. Mutations in SOX2 are...
Genome Res. - issue: 4 - volume: 26 - pages: 474-485.

El Robrini, N.  et al. 2016

Cardiac outflow morphogenesis depends on effects of retinoic acid signaling on multiple cell lineages

Background: Retinoic acid (RA), the bioactive derivative of vitamin A, is essential for vertebrate heart development. Both excess and reduced RA signaling lead to cardiovascular malformations...
Dev. Dyn. - issue: 3 - volume: 245 - pages: 388-401.

Theron, A.  et al. 2016

Krox20 heterozygous mice: A model of aortic regurgitation associated with decreased expression of fibrillar collagen genes

Background. - The mechanism involved in the onset of aortic valve (AoV) disease remains unclear despite its poor prognosis and frequency. Recently, we reported that Krox20 (EGR2 in humans) is involved...
Arch. Cardiovasc. Dis. - issue: 3 - volume: 109 - pages: 188-198.

Escot, S.  et al. 2016

Disruption of CXCR4 signaling in pharyngeal neural crest cells causes DiGeorge syndrome-like malformations

DiGeorge syndrome (DGS) is a congenital disease causing cardiac outflow tract anomalies, craniofacial dysmorphogenesis, thymus hypoplasia, and mental disorders. It results from defective development...
Development - issue: 4 - volume: 143 - pages: 582-588.

Stefanovic, S.  et al. 2015

GATA-dependent transcriptional and epigenetic control of cardiac lineage specification and differentiation

Heart progenitor cells differentiate into various cell types including pacemaker and working cardiomyocytes. Cell-type specific gene expression is achieved by combinatorial interactions between...
Cell. Mol. Life Sci. - issue: 20 - volume: 72 - pages: 3871-3881.

Roux, M.  et al. 2015

Hoxb1 regulates proliferation and differentiation of second heart field progenitors in pharyngeal mesoderm and genetically interacts with Hoxa1 during cardiac outflow tract development

Outflow tract (OFT) anomalies are among the most common congenital heart defects found at birth. The embryonic OFT grows by the progressive addition of cardiac progenitors, termed the second heart...
Dev. Biol. - issue: 2 - volume: 406 - pages: 247-258.

Papoutsi, T.  et al. 2015

Msx1(creERT2) knock-In allele: A useful tool to target embryonic and adult cardiac valves

Heart valve development begins with the endothelial-to-mesenchymal transition (EMT) of endocardial cells. Although lineage studies have demonstrated contributions from cardiac neural crest and...
Genesis - issue: 5 - volume: 53 - pages: 337-345.

Price, HN.  et al. 2015

Practical Application of the New Classification Scheme for Congenital Melanocytic Nevi

A new consensus-based classification of congenital melanocytic nevi (CMN) has recently been proposed. It includes categories for projected adult size (PAS) and location, satellite nevi counts, and...
Pediatr. Dermatol. - issue: 1 - volume: 32 - pages: 23-27.

Odelin, G.  et al. 2014

Loss of Krox20 results in aortic valve regurgitation and impaired transcriptional activation of fibrillar collagen genes

Aims Heart valve maturation is achieved by the organization of extracellular matrix (ECM) and the distribution of valvular interstitial cells. However, the factors that regulate matrix components...
Cardiovasc. Res. - issue: 3 - volume: 104 - pages: 443-455.

Mohan, RA.  et al. 2014

A Mutation in the Kozak Sequence of GATA4 Hampers Translation in a Family With Atrial Septal Defects

Atrial septal defect (ASD) is the most common congenital heart defect clinically characterized by an opening in the atrial septum. Mutations in GATA4, TBX5, and NKX2-5 underlie this phenotype. Here,...
Am. J. Med. Genet. A - issue: 11 - volume: 164 - pages: 2732-2738.

Rana, MS.  et al. 2014

Tbx1 Coordinates Addition of Posterior Second Heart Field Progenitor Cells to the Arterial and Venous Poles of the Heart

Rationale: Cardiac progenitor cells from the second heart field (SHF) contribute to rapid growth of the embryonic heart, giving rise to right ventricular and outflow tract (OFT) myocardium at the...
Circ.Res. - issue: 9 - volume: 115 - pages: 790-U118.

Prados, B.  et al. 2014

Bmp2 patterns prospective valve tissue and regulates EMT and mesenchyme proliferation and morphogenesis

Transgenic Res. - issue: 5 - volume: 23 - pages: 901-901.

Bertrand, N.  et al. 2014

LRRC1 and SCRIB, two polarity genes from the LAP family, genetically interact during embryogenesis

FEBS J. - issue: - volume: 281 - pages: 329-329.

Stefanovic, S.  et al. 2014

GATA-dependent regulatory switches establish atrioventricular canal specificity during heart development

The embryonic vertebrate heart tube develops an atrioventricular canal that divides the atrial and ventricular chambers, forms atrioventricular conduction tissue and organizes valve development. Here...
Nat. Commun. - issue: - volume: 5 - pages: 3680.

Etchevers, HC.  et al. 2014

Hiding in Plain Sight: Molecular Genetics Applied to Giant Congenital Melanocytic Nevi

Large and giant congenital melanocytic nevi are rare malformations that offer surprising insight into prenatal and postnatal acquisition of nevi of any size, central and peripheral nervous system...
- issue: 4 - volume: 134 - pages: 879-882.

Yajima, I.  et al. 2013

A Subpopulation of Smooth Muscle Cells, Derived from Melanocyte-Competent Precursors, Prevents Patent Ductus Arteriosus

Background: Patent ductus arteriosus is a life-threatening condition frequent in premature newborns but also present in some term infants. Current mouse models of this malformation generally lead to...
PLoS One - issue: 1 - volume: 8 - pages: e53183.

Watanabe, Y.  et al. 2012

Fibroblast growth factor 10 gene regulation in the second heart field by Tbx1, Nkx2-5, and Islet1 reveals a genetic switch for down-regulation in the myocardium

During cardiogenesis, Fibroblast Growth Factor (Fgf10) is expressed in the anterior second heart field. Together with Fibroblast growth factor 8 (Fgf8), Fgf10 promotes the proliferation of these...
Proc. Natl. Acad. Sci. U. S. A. - issue: 45 - volume: 109 - pages: 18273-18280.

Faure, E.  et al. 2012

P2Y2 receptor inhibits EGF-induced MAPK pathway to stabilise keratinocyte hemidesmosomes

alpha 6 beta 4 integrin is the main component of hemidesmosomes (HD) that stably anchor the epithelium to the underlying basement membrane. Epithelial cell migration requires HD remodelling, which can...
J. Cell Sci. - issue: 18 - volume: 125 - pages: 4264-4277.

Krupp, DR.  et al. 2012

Transcriptome profiling of genes involved in neural tube closure during human embryonic development using long serial analysis of gene expression (long-SAGE)

BACKGROUND Neural tube defects (NTDs) are common human birth defects with a complex etiology. To develop a comprehensive knowledge of the genes expressed during normal neurulation, we established...
Birth Defects Res. Part A-Clin. Mol. Teratol. - issue: 9 - volume: 94 - pages: 683-692.

Zaffran, S.  et al. 2012

New developments in the second heart field

During cardiac looping the heart tube elongates by addition of progenitor cells from adjacent pharyngeal mesoderm to the arterial and venous poles. This cell population, termed the second heart field,...
Differentiation - issue: 1 - volume: 84 - pages: .

Chassaing, N.  et al. 2012

OTX2 mutations contribute to the otocephaly-dysgnathia complex

Background Otocephaly or dysgnathia complex is characterised by mandibular hypoplasia/agenesis, ear anomalies, microstomia, and microglossia; the molecular basis of this developmental defect is...
J. Med. Genet. - issue: 6 - volume: 49 - pages: 373-379.

Bun, S.  et al. 2012

Value of In Vivo T2 Measurement for Myocardial Fibrosis Assessment in Diabetic Mice at 11.75 T

Objective: The aim of the study was to assess the value of in vivo T2 measurements to noninvasively quantify myocardial fibrosis in diabetic mice at 11.75 T. Diabetic cardiomyopathy is characterized...
Invest. Radiol. - issue: 5 - volume: 47 - pages: 319-323.

Taylor, J.  et al. 2012

Cardiovascular Research Funding: European Molecular Biology Organization Awards

Circulation - issue: 14 - volume: 125 - pages: F79-F83.

Van Der Werf, CS.  et al. 2012

CLMP Is Required for Intestinal Development, and Loss-of-Function Mutations Cause Congenital Short-Bowel Syndrome

BACKGROUND & AIMS: Short-bowel syndrome usually results from surgical resection of the small intestine for diseases such as intestinal atresias, volvulus, and necrotizing enterocolitis. Patients with...
Gastroenterology - issue: 3 - volume: 142 - pages: 453-U98.

Golzio, C.  et al. 2012

ISL1 Directly Regulates FGF10 Transcription during Human Cardiac Outflow Formation

The LIM homeodomain gene Islet-1 (ISL1) encodes a transcription factor that has been associated with the multipotency of human cardiac progenitors, and in mice enables the correct deployment of second...
PLoS One - issue: 1 - volume: 7 - pages: e30677.