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Genetic control of heart development

Our team studies heart development in order to identify biological mechanisms underlying organogenesis, regeneration and congenital disease.

Learning how organs form in the embryo is essential to understand the origins of congenital disease and to develop approaches for repairing adult tissue after damage. The heart is the first organ to form and function in the embryo and cardiac development involves complex interactions between genes, progenitor cell populations and inter-cellular signaling events. This complexity is reflected in the fact that congenital heart defects affect 1 in 100 births. Our group studies heart development in the mouse, where the developmental sequence of events is very similar to that in humans, focusing on two critical areas.

Firstly, we investigate the growth of the embryonic heart by progressive addition of myocardium from progenitor cells known as the second heart field (SHF). SHF derived parts of the heart are hotspots for common congenital heart defects. We study the properties of SHF cells and the mechanisms driving their deployment to the heart. The genetic program of the SHF is shared with head muscle progenitor cells, and we also investigate how a common program diverges to give rise to heart and head muscle.

Secondly, we study the development of the cardiac conduction system that forms the electrical wiring of the heart and coordinates the heartbeat. The conduction system is derived from common progenitor cells with contractile cardiomyoctyes of the heart and we investigate the cellular and genetic mechanisms required for the establishment of these specialized myocytes during normal development and under pathological conditions.

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Immunofluorescence showing gene expression in the heart and adjacent pharyngeal apparatus in a sagittal section of a mouse embryo at embryonic day 9.5. The expression of Tbx1 (pharyngeal mesoderm and endoderm) is shown in blue, Isl1 (second heart field and pharyngeal epithelia) in green, Vegfr2 (endothelial cells) in red and nuclei in grey. Blood cells appear in yellow (picture: Estelle Jullian).

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Team members

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Alumni

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Adachi Noritaka
Assistant Professor, Tokyo Medical and Dental University, Tokyo, Japan
Choquet Caroline
Post-doc, Lescroart lab, Marseille Medical Genetics Unit, Inserm UMR_S910, Medical School, Aix-Marseille University, Marseille
Cortes Claudio
Post-doc, Riley lab, Department of Physiology, Anatomy & Genetics, University of Oxford, UK
De Bono Christopher
Post-doc, Morrow lab, Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA
Francou Alexandre
Post-doc, Hadjantonakis lab, Memorial Sloan Kettering Cancer Center, SKI, Developmental Biology Department, 430 E 67th St, New York, NY10065, USA
Mesbah Karim
Manager of the functional exploration platform at the l’IGF-IGH, Montpellier.
Rochais Francesca
Group leader, Marseille Medical Genetics Unit, Inserm UMRS910, Medical School, Aix-Marseille University, Marseille
Theveniau-Ruissy, Magali
Research Scientist, Rochais lab, Marseille Medical Genetics Unit, Inserm UMRS910, Medical School, Aix-Marseille University, Marseille

Funding bodies

They support our research
ARN
Fondation Recherche Medicale

Gallery

Wholemount high magnification view of a mouse heart showing labeled fluorescent cell clusters in ventricular myocardium after recombination of a Confetti reporter cassette with Mesp1-Cre recombinase (picture: Caroline Choquet).
Wholemount view of the ellipsoid Purkinje fibre network of specialised fast-conducting myocytes on the luminal surface of a mouse heart labeled with Connexin40-GFP (picture: Lucie Boulgakoff).
Wholemount lightsheet microscopy image of a mouse heart after myocardial infarction showing coronary arteries (red), Purkinje fibres in the right (blue) and left (green) ventricles and CD45+ immune cells (grey) at the site of damage (picture: Lucie Boulgakoff).
Composite view of epithelial second heart field cells in the dorsal pericardical wall at embryonic day 9.5 showing nuclei, golgi, apical actin filaments, cell contours and colour-coded apical surface (picture: Clara Guijarro-Calvo)
Whole mouse fluorescent in situ hybridisation of a mouse embryo at E7.5 showing Tbx1 expression in pharyngeal mesoderm (green) and Nkx2-5 expression in the cardiac crescent (picture: Camille Dumas).

Genetic control of heart development

Our team studies heart development in order to identify biological mechanisms underlying organogenesis, regeneration and congenital disease.

Second heart field cardiac progenitor cells

The SHF, identified 20 years ago, is a population of cardiac progenitor cells in pharyngeal mesoderm of the early embryo that gives rise to the right ventricle and outflow tract at the arterial pole of the heart, and atrial myocardium at the venous pole. Perturbation of SHF deployment impacts on later stages of development and leads to defects in atrial, ventricular and outflow tract septation that account for the majority of CHDs.

Our research project focuses on the genetic regulation, epithelial nature and dynamic behavior of SHF cells in the early embryo. Different regions of the heart are pre-patterned within the SHF and we use mouse genetics to study gene function and lineage contributions, together with quantitative imaging, embryo and explant culture, and transcriptomic approaches. We focus on how the regulatory factor TBX1 controls development of a subpopulation of SHF cells that give rise to myocardium at the arterial pole of the heart. TBX1 is the major candidate gene for 22q11.2 deletion (or DiGeorge) syndrome (1 in 4000 live births), a common cause of outflow tract malformations in man. We are investigating the mechanisms that regulate the segregation of SHF cells into TBX1 positive arterial pole progenitor cells and venous pole progenitors, expressing a second T-box gene TBX5, mutations in which cause Holt-Oram syndrome. Moreover we are addressing the currently poorly understood mechanisms by which atrial and ventricular septal structures arise at the interface between TBX1 and TBX5 expressing progenitor populations.

RNAscope fluorescent in situ hybridisation of a mouse embryo at embryonic day 7.5 showing early cardiomyocytes (red) and cardiopharyngeal mesoderm (green).
RNAscope fluorescent in situ hybridisation of a mouse embryo at embryonic day 7.5 showing early cardiomyocytes (red) and cardiopharyngeal mesoderm (green).

Pharyngeal mesoderm is the source not only of cardiac muscle but also of a subset of skeletal muscles of the head and neck, known as branchiomeric muscles. These muscles are specified in the core of the pharyngeal arches at midgestation and regulate jaw opening and closure, facial expression and pharyngeal and laryngeal function. They differ fundamentally from somite derived muscles that constitute the body and limb musculature. Branchiomeric skeletal muscle progenitor cells are dependent on Tbx1 and develop from a common cardiopharyngeal progenitor population with SHF derived parts of the heart. Our experiments address how divergent myogenic fates arise within this cardiopharyngeal developmental field.

Wiring the ventricles

Polyclonal growth of the ventricular conduction system.
Polyclonal growth of the ventricular conduction system.

The ventricular conduction system (VCS) coordinates the heartbeat and ensures rapid transmission of the electrical signal to the apex of the heart to initiate ventricular contraction. We are using clonal analysis and genetic tracing to study the development of these specialized cardiomyocytes. We are also generating and characterizing mouse models with defective conduction system morphology and function. We are focusing on the development of trabeculae, transient sponge-like myocardial projections in the fetal heart, which represent progenitor cells of the VCS. Persistence of trabeculae results in ventricular non-compaction, associated with conduction anomalies, in human patients.