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Hox-Dependent Coordination of Cardiac Cell Patterning and Differentiation

49 Pages Posted: 6 Feb 2019 Sneak Peek Status: Under Review

See all articles by Sonia Stefanovic

Sonia Stefanovic

Aix-Marseille University - Marseille Medical Genetics

Brigitte Laforest

Aix-Marseille University - Marseille Medical Genetics

Jean-Pierre Desvignes

Aix-Marseille University - Marseille Medical Genetics

Fabienne Lescroart

Aix-Marseille University - Marseille Medical Genetics

Laurent Argiro

Aix-Marseille University - Marseille Medical Genetics

Corinne Maurel-Zaffran

Aix-Marseille University - Institut de Biologie du Développement de Marseille (IBDM)

David Salgado

Aix-Marseille University - Marseille Medical Genetics

Christopher de Bono

Aix-Marseille University - Institut de Biologie du Développement de Marseille (IBDM)

Kristijan Pazur

Dresden University of Technology - Paul Langerhans Institute Dresden (PLID)

Magali Théveniau-Ruissy

Aix-Marseille University - Institut de Biologie du Développement de Marseille (IBDM)

Christophe Béroud

Aix-Marseille University - Marseille Medical Genetics

Michel Pucéat

Aix-Marseille University - Marseille Medical Genetics

Anthony Gavalas

Dresden University of Technology - Paul Langerhans Institute Dresden (PLID)

Robert G. Kelly

Aix-Marseille University - Institut de Biologie du Développement de Marseille (IBDM)

Stephane Zaffran

Aix-Marseille University - Marseille Medical Genetics

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Abstract

During early cardiogenesis, progressive addition of distinct cardiac progenitor cells originating from the second heart field (SHF) contributes to elongation of the forming heart. Whereas the subdivision of the SHF into an anterior and posterior domain is essential for morphogenesis of the definitive heart, the transcriptional programs and upstream regulatory events operating in the different progenitor cell populations remain unclear. Here, we characterize the molecular signature and regulation of anterior and posterior sub-populations of SHF cells. We profiled the transcriptome and chromatin accessibility of purified sub-populations at genome-wide levels and demonstrated that the transcriptional regulator Hoxb1 controls the differentiation of the posterior SHF progenitors during heart morphogenesis. Spatial mis-expression of Hoxb1 in anterior SHF progenitors that normally contribute to right ventricular cardiomyocytes results in hypoplastic right ventricle, revealing how deregulation of a specific sub-population of the SHF can result in congenital heart defects. Expanded activation of Hoxb1 perturbs the anterior transcriptional program and induces increased progenitor cell death in anterior SHF progenitors. Moreover, activation of Hoxb1 in embryonic stem cells arrests cardiac differentiation, whereas Hoxb1-deficient embryos display premature differentiation of cardiac progenitor cells. Our results show that Hoxb1 coordinates a cascade of gene-regulatory events in the SHF essential for proper heart development and provide new insights into how deregulation of SHF sub-population identities can induce congenital heart defects.

Keywords: SHF; progenitor cell; cardiac differentiation; patterning; Hox; heart development; mouse embryo

Suggested Citation

Stefanovic, Sonia and Laforest, Brigitte and Desvignes, Jean-Pierre and Lescroart, Fabienne and Argiro, Laurent and Maurel-Zaffran, Corinne and Salgado, David and Bono, Christopher de and Pazur, Kristijan and Théveniau-Ruissy, Magali and Béroud, Christophe and Pucéat, Michel and Gavalas, Anthony and Kelly, Robert G. and Zaffran, Stephane, Hox-Dependent Coordination of Cardiac Cell Patterning and Differentiation (February 6, 2019). Available at SSRN: https://ssrn.com/abstract=3329886 or http://dx.doi.org/10.2139/ssrn.3329886
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Sonia Stefanovic

Aix-Marseille University - Marseille Medical Genetics

3 Avenue Robert Schuman
Aix-en-Provence, 13628
France

Brigitte Laforest

Aix-Marseille University - Marseille Medical Genetics

3 Avenue Robert Schuman
Aix-en-Provence, 13628
France

Jean-Pierre Desvignes

Aix-Marseille University - Marseille Medical Genetics

3 Avenue Robert Schuman
Aix-en-Provence, 13628
France

Fabienne Lescroart

Aix-Marseille University - Marseille Medical Genetics

3 Avenue Robert Schuman
Aix-en-Provence, 13628
France

Laurent Argiro

Aix-Marseille University - Marseille Medical Genetics

3 Avenue Robert Schuman
Aix-en-Provence, 13628
France

Corinne Maurel-Zaffran

Aix-Marseille University - Institut de Biologie du Développement de Marseille (IBDM)

163 Avenue de Luminy
Marseille, 13009
France

David Salgado

Aix-Marseille University - Marseille Medical Genetics

3 Avenue Robert Schuman
Aix-en-Provence, 13628
France

Christopher de Bono

Aix-Marseille University - Institut de Biologie du Développement de Marseille (IBDM)

163 Avenue de Luminy
Marseille, 13009
France

Kristijan Pazur

Dresden University of Technology - Paul Langerhans Institute Dresden (PLID)

Einsteinstrasse 3
Dresden, 01062
Germany

Magali Théveniau-Ruissy

Aix-Marseille University - Institut de Biologie du Développement de Marseille (IBDM)

163 Avenue de Luminy
Marseille, 13009
France

Christophe Béroud

Aix-Marseille University - Marseille Medical Genetics

3 Avenue Robert Schuman
Aix-en-Provence, 13628
France

Michel Pucéat

Aix-Marseille University - Marseille Medical Genetics

3 Avenue Robert Schuman
Aix-en-Provence, 13628
France

Anthony Gavalas

Dresden University of Technology - Paul Langerhans Institute Dresden (PLID)

Einsteinstrasse 3
Dresden, 01062
Germany

Robert G. Kelly

Aix-Marseille University - Institut de Biologie du Développement de Marseille (IBDM)

163 Avenue de Luminy
Marseille, 13009
France

Stephane Zaffran (Contact Author)

Aix-Marseille University - Marseille Medical Genetics ( email )

3 Avenue Robert Schuman
Aix-en-Provence, 13628
France

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