Genetic control of heart development

Group leader : R. Kelly

Our group addresses how different progenitor populations contribute in an integrated manner to the definitive heart and how these processes are regulated by genes and intercellular signalling pathways.


The heart is the first organ to function in the embryo and cardiac development involves complex interactions between multiples genes, progenitor cell populations and signalling events. This complexity is reflected in the fact that defects in heart development result in congenital anomalies affecting 1% of live births.

Our group studies the genetic control of heart development, focusing on two critical processes:

Firstly, we are investigating the progressive formation of the embryonic heart by addition of myocardium to the poles of the heart tube, from progenitor cells in pharyngeal mesoderm termed the second heart field. This recently discovered population of progenitor cells gives rise to a large part of the definitive heart including the right ventricle, outflow tract and part of the atria.

Robert Kelly Team studying cardiac and heart development cardiac stem cell and digeorge syndrome at IBDM, IBDML

Cartoon showing addition of second heart field progenitor cells (blue) to the arterial and venous poles of the heart tube between embryonic days (E) 7.5 and 10.5 of mouse development.

The outflow tract is a major hotspot for common forms of congenital heart defects. We are investigating the properties of second heart field cells and the regulatory mechanisms that control their addition to the heart tube, including the role of the DiGeorge syndrome gene Tbx1. The genetic program of the second heart field is shared with pharyngeal mesodermal cells giving rise to skeletal muscles of the head and we are also addressing how a single progenitor cell population gives rise to divergent cardiac and skeletal muscle fates.

The cardiac conduction system drawing, by Robert Kelly team, for the cardiax and heart development comprehension.

Cartoon showing the specialised cardiac conduction system: yellow, sinoatrial node or pacemaker; blue, atrioventricular node; green, ventricular conduction system. White arrows indicate the direction of electrical conduction.

Secondly, we are studying the establishment of the cardiac conduction system. This constitutes the electrical wiring of the heart and coordinates the heartbeat. Using a variety of genetic approaches in mice we are investigating the origins and establishment of these specialized myocytes, during normal development and in pathological situations.

Studying heart development in the mouse provides both basic insights into the mechanisms underlying organogenesis and biomedically relevant findings. These include insights into the etiology of congenital heart defects and conduction anomalies, as well as into the properties of cardiac progenitors cells relevant for the repair and regeneration of damaged hearts.


Our group addresses how different progenitor populations contribute in an integrated manner to the definitive heart and how these processes are regulated by genes and intercellular signalling pathways.

1. Second heart field cardiac progenitor cells

coronary artery anomalies in a Tbx1 null heart picture by Robert Kelly team (digeorge syndrome)

Connexin40-GFP expression in coronary endothelial cells showing abnormal patterning of the coronary arteries in the ventral region of the heart.

The second heart field is a recently identified population of cardiac progenitor cells located in pharyngeal mesoderm that gives rise to atrial myocardium, the right ventricle and the outflow tract of the heart, a region affected in 30% of congenital heart defects. We are investigating the genetic regulation, epithelial nature and dynamic behaviour of second heart field progenitor cells in the early mouse embryo. Different regions of the heart are pre-patterned within the second heart field and we are studying how the transcription factor TBX1 controls development of a subpopulation of progenitor cells that give rise to myocardium at the outlet of the right ventricle. TBX1 is the major candidate gene for DiGeorge syndrome (1 in 4000 live births), a common cause of outflow tract malformation in man. We are also studying how defects in early steps of heart morphogenesis impact on later stages of development including outflow tract septation, coronary arteriogenesis and ventricular growth.

2. Connecting heart and head muscle development

Robert Kelly team from IBDM shows the importance of tbx1 in digeorge syndrome.

Expression profile of an Fgf10-lacZ reporter transgene visualized after X-gal staining in an E14.5 mouse embryo showing transgene expression in Tbx1-dependent craniofacial skeletal muscles.

Pharyngeal mesoderm is the source not only of cardiac muscle but also of a subset of craniofacial skeletal muscles, 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 dependant on Tbx1 and develop from a common pharyngeal mesodermal progenitor population with second heart field derived parts of the heart. We are investigating how divergent myogenic fates arise within pharyngeal mesoderm and the role of Tbx1 in this cardiocraniofacial developmental field.

3. Wiring the ventricles

The ventricular conduction system important for cardiac development in mus musculus

Expression of a Connexin40-eGFP reporter gene in ventricular conduction system, showing the ellipsoid structures composing the Purkinje fiber network.

The ventricular conduction system 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 specialised cardiomyocytes. We are also generating and characterizing mouse models with defective conduction system morphology and function. The development of trabeculae, transient sponge-like myocardial projections in the fetal heart, is also under analysis. Persistence of trabeculae results in ventricular non-compaction, associated with conduction anomalies, in human patients.

Selected publications


Cardiopharyngeal mesoderm origins of musculoskeletal and connective tissues in the mammalian pharynx.

Adachi N, Bilio M, Baldini A, Kelly RG.
Development. 2020 Feb 3;147(3). PMID: 32014863


Epithelial tension in the second heart field promotes mouse heart tube elongation.

Francou A, De Bono C, Kelly RG.
Nat Commun. 2017 Mar 30;8:14770. PMID: 28357999


Coronary stem development in wildtype and Tbx1 null mouse hearts.

Théveniau-Ruissy M, Pérez-Pomares JM, Parisot P, Baldini A, Miquerol L, Kelly RG.
Dev Dyn. 2015 Dec 28. doi: 10.1002/dvdy.24380. PMID: 26708418


A Cranial Mesoderm Origin for Esophagus Striated Muscles.

Gopalakrishnan S, Comai G, Sambasivan R, Francou A, Kelly RG, Tajbakhsh S.
Dev Cell. 2015 Sep 28;34(6):694-704. PMID: 26387456


Endothelial Plasticity Drives Arterial Remodeling Within the Endocardium After Myocardial Infarction

Miquerol L, Thireau J, Bideaux P, Sturny R, Richard S, Kelly RG.
Circ Res. 2015 May 22;116(11):1765-71. PMID: 25834185


A new heart for a new head in vertebrate cardiopharyngeal evolution.

Diogo R, Kelly RG, Christiaen L, Levine M, Ziermann JM, Molnar JL, Noden DM, Tzahor E.
Nature. 2015 Apr 23;520(7548):466-73. PMID: 25903628


FGF10 promotes regional foetal cardiomyocyte proliferation and adult cardiomyocyte cell-cycle re-entry.

Rochais F, Sturny R, Chao CM, Mesbah K, Bennett M, Mohun TJ, Bellusci S, Kelly RG.
Cardiovasc Res. 2014 Dec 1;104(3):432-42. PMID: 25344367


TBX1 regulates epithelial polarity and dynamic basal filopodia in the second heart field.

Francou A, Saint-Michel E, Mesbah K, Kelly RG.
Development. 2014 Nov;141(22):4320-31. doi: 10.1242/dev.115022. PMID: 25371366


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

Rana MS, Théveniau-Ruissy M, De Bono C, Mesbah K, Francou A, Rammah M, Domínguez JN, Roux M, Laforest B, Anderson RH, Mohun T, Zaffran S, Christoffels VM, Kelly RG.
Circ Res. 2014 Oct 10;115(9):790-9. PMID: 25190705


Organogenesis of the vertebrate heart.

Miquerol L, Kelly RG.
Wiley Interdiscip Rev Dev Biol. 2013 Jan;2(1):17-29. PMID: 23799628


The second heart field.

Kelly RG.
Curr Top Dev Biol. 2012;100:33-65. PMID: 22449840


Biphasic development of the mammalian ventricular conduction system.

Miquerol L, Moreno-Rascon N, Beyer S, Dupays L, Meilhac SM, Buckingham ME, Franco D, Kelly RG.
Circ Res. 2010 Jul 9;107(1):153-61. PMID: 20466980


How Mesp1 makes a move

Kelly RG.
J Cell Biol. 2016 May 23;213(4):411-3. PMID: 27185831


Revascularization of the heart after infarct: lessons from embryonic development.

Miquerol L.
Med Sci (Paris). 2016 Feb;32(2):158-62. PMID: 26936172


Congenital coronary artery anomalies: a bridge from embryology to anatomy and pathophysiology--a position statement of the development, anatomy, and pathology ESC Working Group.

Pérez-Pomares JM, de la Pompa JL, Franco D, Henderson D, Ho SY, Houyel L, Kelly RG, Sedmera D, Sheppard M, Sperling S, Thiene G, van den Hoff M, Basso C.
Cardiovasc Res. 2016 Feb 1;109(2):204-16. PMID: 26811390


Adhesive Enrichment and Membrane Turnover at the Heart of Cardiopharyngeal Induction.

Kelly RG.
Dev Cell. 2015 Sep 14;34(5):490-2. PMID: 26374763


Optogenetic determination of the myocardial requirements for extrasystoles by cell type-specific targeting of ChannelRhodopsin-2.

Zaglia T, Pianca N, Borile G, Da Broi F, Richter C, Campione M, Lehnart SE, Luther S, Corrado D, Miquerol L, Mongillo M.
Proc Natl Acad Sci U S A. 2015 Aug 11;112(32):E4495-504. PMID: 26204914


Loss of Wnt5a disrupts second heart field cell deployment and may contribute to OFT malformations in DiGeorge syndrome.

Sinha T, Li D, Théveniau-Ruissy M, Hutson MR, Kelly RG, Wang J.
Hum Mol Genet. 2015 Mar 15;24(6):1704-16. PMID: 25410658


Clonal analysis reveals a common origin between nonsomite-derived neck muscles and heart myocardium.

Lescroart F, Hamou W, Francou A, Théveniau-Ruissy M, Kelly RG, Buckingham M.
Proc Natl Acad Sci U S A. 2015 Feb 3;112(5):1446-51. PMID: 25605943


Prdm1 functions in the mesoderm of the second heart field, where it interacts genetically with Tbx1, during outflow tract morphogenesis in the mouse embryo

Vincent SD, Mayeuf-Louchart A, Watanabe Y, Brzezinski JA, Miyagawa-Tomita S, Kelly RG, Buckingham M.
Hum Mol Genet. 2014 Oct 1;23(19):5087-101. PMID: 24821700


Heart fields and cardiac morphogenesis.

Kelly RG, Buckingham ME, Moorman AF.
Cold Spring Harb Perspect Med. 2014 Oct 1;4(10). PMID: 25274757


Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation.

Mesirca P, Alig J, Torrente AG, Müller JC, Marger L, Rollin A, Marquilly C, Vincent A, Dubel S, Bidaud I, Fernandez A, Seniuk A, Engeland B, Singh J, Miquerol L, Ehmke H, Eschenhagen T, Nargeot J, Wickman K, Isbrandt D, Mangoni ME.
Nat Commun. 2014 Aug 21;5:4664. PMID: 25144323


Resolving cell lineage contributions to the ventricular conduction system with a Cx40-GFP allele: a dual contribution of the first and second heart fields.

Miquerol L, Bellon A, Moreno N, Beyer S, Meilhac SM, Buckingham M, Franco D, Kelly RG.
Dev Dyn. 2013 Jun;242(6):665-77. PMID: 23526457


Second heart field cardiac progenitor cells in the early mouse embryo.

Francou A, Saint-Michel E, Mesbah K, Théveniau-Ruissy M, Rana MS, Christoffels VM, Kelly RG.
Biochim Biophys Acta. 2013 Apr;1833(4):795-8. PMID: 23051926


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.

Watanabe Y, Zaffran S, Kuroiwa A, Higuchi H, Ogura T, Harvey RP, Kelly RG, Buckingham M.
Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18273-80. PMID: 23093675


The effect of connexin40 deficiency on ventricular conduction system function during development.

Sankova B, Benes J Jr, Krejci E, Dupays L, Theveniau-Ruissy M, Miquerol L, Sedmera D.
Cardiovasc Res. 2012 Sep 1;95(4):469-79. PMID: 22739121


Epistatic rescue of Nkx2.5 adult cardiac conduction disease phenotypes by prospero-related homeobox protein 1 and HDAC3.

Risebro CA, Petchey LK, Smart N, Gomes J, Clark J, Vieira JM, Yanni J, Dobrzynski H, Davidson S, Zuberi Z, Tinker A, Shui B, Tallini YI, Kotlikoff MI,Miquerol L, Schwartz RJ, Riley PR.
Circ Res. 2012 Jul 6;111(2):e19-31. PMID: 22647876


New developments in the second heart field.

Zaffran S, Kelly RG.
Differentiation. 2012 Jul;84(1):17-24. PMID: 22521611


Remodeling of the peripheral cardiac conduction system in response to pressure overload.

Harris BS, Baicu CF, Haghshenas N, Kasiganesan H, Scholz D, Rackley MS, Miquerol L, Gros D, Mukherjee R, O'Brien TX.
Am J Physiol Heart Circ Physiol. 2012 Apr 15;302(8):H1712-25. PMID: 22307665


Identification of a Tbx1/Tbx2/Tbx3 genetic pathway governing pharyngeal and arterial pole morphogenesis.

Mesbah K, Rana MS, Francou A, van Duijvenboden K, Papaioannou VE, Moorman AF, Kelly RG, Christoffels VM.
Hum Mol Genet. 2012 Mar 15;21(6):1217-29. PMID: 22116936


Irx3: a conductor of conduction.

Kelly RG.
Circ Res. 2011 Oct 14;109(9):984-5. PMID: 21998297


Contemporary cardiogenesis: new insights into heart development.

Franco D, Kelly RG.
Cardiovasc Res. 2011 Jul 15;91(2):183-4. PMID: 21632879


Establishment of the mouse ventricular conduction system.

Miquerol L, Beyer S, Kelly RG.
Cardiovasc Res. 2011 Jul 15;91(2):232-42. PMID: 21385837


Tbx1, subpulmonary myocardium and conotruncal congenital heart defects.

Parisot P, Mesbah K, Théveniau-Ruissy M, Kelly RG.
Birth Defects Res A Clin Mol Teratol. 2011 Jun;91(6):477-84. PMID: 21591244


Inducible Cx40-Cre expression in the cardiac conduction system and arterial endothelial cells.

Beyer S, Kelly RG, Miquerol L.
Genesis. 2011 Feb;49(2):83-91. PMID: 21344610


Core issues in craniofacial myogenesis.

Kelly RG.
Exp Cell Res. 2010 Nov 1;316(18):3034-41. PMID: 20457151


Clonal analysis reveals common lineage relationships between head muscles and second heart field derivatives in the mouse embryo.

Lescroart F, Kelly RG, Le Garrec JF, Nicolas JF, Meilhac SM, Buckingham M.
Development. 2010 Oct;137(19):3269-79. PMID: 20823066


Hes1 expression is reduced in Tbx1 null cells and is required for the development of structures affected in 22q11 deletion syndrome.

van Bueren KL, Papangeli I, Rochais F, Pearce K, Roberts C, Calmont A, Szumska D, Kelly RG, Bhattacharya S, Scambler PJ.
Dev Biol. 2010 Apr 15;340(2):369-80. PMID: 20122914


Decreased levels of embryonic retinoic acid synthesis accelerate recovery from arterial growth delay in a mouse model of DiGeorge syndrome.

Ryckebüsch L, Bertrand N, Mesbah K, Bajolle F, Niederreither K, Kelly RG, Zaffran S.
Circ Res. 2010 Mar 5;106(4):686-94. PMID: 20110535


Role of mesodermal FGF8 and FGF10 overlaps in the development of the arterial pole of the heart and pharyngeal arch arteries.

Watanabe Y, Miyagawa-Tomita S, Vincent SD, Kelly RG, Moon AM, Buckingham ME.
Circ Res. 2010 Feb 19;106(3):495-503. PMID: 20035084


Megavoltage planar and cone-beam imaging with low-Z targets: dependence of image quality improvement on beam energy and patient separation.

Robar JL, Connell T, Huang W, Kelly RG.
Med Phys. 2009 Sep;36(9):3955-63. PMID: 19810468


Hes1 is expressed in the second heart field and is required for outflow tract development.

Rochais F, Dandonneau M, Mesbah K, Jarry T, Mattei MG, Kelly RG.
PLoS One. 2009 Jul 17;4(7):e6267. PMID: 19609448


Monitoring clonal growth in the developing ventricle.

Miquerol L, Kelly RG.


Distinct regulatory cascades govern extraocular and pharyngeal arch muscle progenitor cell fates.

Sambasivan R, Gayraud-Morel B, Dumas G, Cimper C, Paisant S, Kelly RG, Tajbakhsh S.
Dev Cell. 2009 Jun;16(6):810-21. PMID: 19531352


Signaling pathways controlling second heart field development.

Rochais F, Mesbah K, Kelly RG.
Circ Res. 2009 Apr 24;104(8):933-42. PMID: 19390062


Relationship between neural crest cells and cranial mesoderm during head muscle development.

Grenier J, Teillet MA, Grifone R, Kelly RG, Duprez D.
PLoS One. 2009;4(2):e4381. PMID: 19198652


Properties of branchiomeric and somite-derived muscle development in Tbx1 mutant embryos.

Grifone R, Jarry T, Dandonneau M, Grenier J, Duprez D, Kelly RG.
Dev Dyn. 2008 Oct;237(10):3071-8. PMID: 18816853


Tbx3 is required for outflow tract development.

Mesbah K, Harrelson Z, Théveniau-Ruissy M, Papaioannou VE, Kelly RG.
Circ Res. 2008 Sep 26;103(7):743-50. PMID: 18723448


The del22q11.2 candidate gene Tbx1 controls regional outflow tract identity and coronary artery patterning.

Théveniau-Ruissy M, Dandonneau M, Mesbah K, Ghez O, Mattei MG, Miquerol L, Kelly RG.
Circ Res. 2008 Jul 18;103(2):142-8. PMID: 18583714


Integration of embryonic and fetal skeletal myogenic programs at the myosin light chain 1f/3f locus.

Zammit PS, Cohen A, Buckingham ME, Kelly RG.
Dev Biol. 2008 Jan 1;313(1):420-33. PMID: 18062958


Myocardium at the base of the aorta and pulmonary trunk is prefigured in the outflow tract of the heart and in subdomains of the second heart field.

Bajolle F, Zaffran S, Meilhac SM, Dandonneau M, Chang T, Kelly RG, Buckingham ME.
Dev Biol. 2008 Jan 1;313(1):25-34. PMID: 18005956


Heartening news for head muscle development.

Grifone R, Kelly RG.
Trends Genet. 2007 Aug;23(8):365-9. PMID: 17524520


Building the right ventricle.

Kelly RG.
Circ Res. 2007 Apr 13;100(7):943-5. PMID: 17431196


Visualization of outflow tract development in the absence of Tbx1 using an FgF10 enhancer trap transgene.

Kelly RG, Papaioannou VE.
Dev Dyn. 2007 Mar;236(3):821-8.


From developmental biology to heart repair.

Campione M, Moorman AF, Kelly RG.
Cell Mol Life Sci. 2007 Mar;64(6):643-5. PMID: 17380305


Congenital heart defects in Fgfr2-IIIb and Fgf10 mutant mice.

Marguerie A, Bajolle F, Zaffran S, Brown NA, Dickson C, Buckingham ME, Kelly RG.
Cardiovasc Res. 2006 Jul 1;71(1):50-60. PMID: 16687131


Left and right ventricular contributions to the formation of the interventricular septum in the mouse heart.

Franco D, Meilhac SM, Christoffels VM, Kispert A, Buckingham M, Kelly RG.
Dev Biol. 2006 Jun 15;294(2):366-75. PMID: 16677630


Rotation of the myocardial wall of the outflow tract is implicated in the normal positioning of the great arteries.

Bajolle F, Zaffran S, Kelly RG, Hadchouel J, Bonnet D, Brown NA, Buckingham ME.
Circ Res. 2006 Feb 17;98(3):421-8. PMID: 16397144


Molecular inroads into the anterior heart field.

Kelly RG.
Trends Cardiovasc Med. 2005 Feb;15(2):51-6. PMID: 15885570


T-box genes in vertebrate development.

Naiche LA, Harrelson Z, Kelly RG, Papaioannou VE.
Annu Rev Genet. 2005;39:219-39. PMID: 16285859


The del22q11.2 candidate gene Tbx1 regulates branchiomeric myogenesis.

Kelly RG, Jerome-Majewska LA, Papaioannou VE.
Hum Mol Genet. 2004 Nov 15;13(22):2829-40. PMID: 15385444


Tbx2 is essential for patterning the atrioventricular canal and for morphogenesis of the outflow tract during heart development.

Harrelson Z, Kelly RG, Goldin SN, Gibson-Brown JJ, Bollag RJ, Silver LM, Papaioannou VE.
Development. 2004 Oct;131(20):5041-52. PMID: 15459098


The clonal origin of myocardial cells in different regions of the embryonic mouse heart.

Meilhac SM, Esner M, Kelly RG, Nicolas JF, Buckingham ME.
Dev Cell. 2004 May;6(5):685-98. PMID: 15130493


Cell history determines the maintenance of transcriptional differences between left and right ventricular cardiomyocytes in the developing mouse heart.

Kelly RG, Lemonnier M, Zaffran S, Munk A, Buckingham ME.
J Cell Sci. 2003 Dec 15;116(Pt 24):5005-13. PMID: 14625394


The anterior heart-forming field: voyage to the arterial pole of the heart.

Kelly RG, Buckingham ME.
Trends Genet. 2002 Apr;18(4):210-6. PMID: 11932022


The arterial pole of the mouse heart forms from Fgf10-expressing cells in pharyngeal mesoderm.

Kelly RG, Brown NA, Buckingham ME.
Dev Cell. 2001 Sep;1(3):435-40. PMID: 11702954


  • Zaffran group, Inserm UMR_S910 Medical School, Aix-Marseille University, Marseille
  • Monique Bernard, CRNBM, Medical School, Aix Marseille University
  • Francesca Rochais, Inserm UMR S910, Medical School, Aix-Marseille University, Marseille
  • Shahragim Tajbakhsh, Institut Pasteur, Paris
  • Antonio Baldini, Institute of Genetics and Biophysics, Naples
  • David Sedmera, Charles University, Prague
  • Silke Sperling, Charité, Berlin


ANR funding for Robert Kelly Team who study cardiac stem cell in mus musculus at IBDM FRM funding for Robert Kelly Team who study cardiac development in mus musculus



Members more

  Julien Fromonot Clara Guijarro Calvo     Lucie Boulgakoff Camille Dumas Lucile Miquerol Rachel Sturny Charlotte Thellier
Robert Kelly
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Robert Kelly


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marie Couderc

MSc student

Julien Fromonot
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Julien Fromonot


Clara Guijarro Calvo
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Clara Guijarro Calvo

PhD student

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Noritaka Adachi

Postdoctoral fellow

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Nicolas Bertrand

University lecturer

Lucie Boulgakoff
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Lucie Boulgakoff

PhD student

Camille Dumas
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Camille Dumas

PhD student

Lucile Miquerol
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Lucile Miquerol


Lucile’s research projects concern the development of the ventricular conduction system to address the question: how does the heart beat in rhythm? We employ genetic tools to perform lineage analysis of the ventricular conduction system and to study the development of the conduction system in embryos with congenital heart diseases. The use of the Cre-Lox system in combination with conditional reporter mice allows us to visualize and trace the conduction system and its progenitors to understand when these cells diverge from the myocardium and what is happening during pathological conditions.

Rachel Sturny
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Rachel Sturny

Technical staff

Charlotte Thellier
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Charlotte Thellier

PhD student


Model organism
Biological process studied
  • Genetic control of heart development
Biological techniques
  • Transgenic and mutant mice
  • Clonal analysis
  • Genetic tracing
Medical applications
  • DiGeorge syndrome
  • Congenital heart disease
  • Cardiac regenerative medicine