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  • Technician
  • Undergraduate Student
  • Veterinary
  • Visiting Scientist
  • Deputy Director of Center
  • Deputy Director of Department
  • Deputy Director of National Reference Center
  • Deputy Head of Facility
  • Director of Center
  • Director of Department
  • Director of Institute
  • Director of National Reference Center
  • Group Leader
  • Head of Facility
  • Head of Operations
  • Head of Structure
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  • Labex Coordinator
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Scientific Fields
Diseases
Organisms
Applications
Technique
Starting Date
01
Jan 2004
Ending Date
31
Dec 2019
Status
Ongoing
Members
3
Structures
1

About

Growth of the heart is required to adapt to the increasing hemodynamic load of the developing organism. Physiologically, heart growth is mainly driven by the proliferation of myocardial cells in utero and by cell size increase after birth. However, how myocardial cells cease to proliferate after birth remains poorly understood. In addition to growing in size, the myocardium matures in its architecture, with the alignment of cardiomyocytes into fibres. This orientation is an important aspect of the efficient heart contraction. A current question is to understand how the architecture of the myocardium is established.

We have previously characterised, by clonal analysis, the lineages and behaviour of myocardial cells during heart morphogenesis.

2_clone.png
Meilhac et al., 2004 – Clone of β-galactosidase positive cardiomyocytes showing the oriented growth of the embryonic myocardium

We have developed interdisciplinary tools for the quantification of tissue anisotropy in 3D and revealed that myocardial cells coordinate locally their orientation of division during cardiac chamber expansion.

3a_e135_div3.png3b_e85_oriented_divisions.png

Le Garrec et al., 2013– Oriented cell divisions in the developing heart

Recently, we have studied the atypical cadherin Fat4, which was initially discovered in the fly as a major regulator of organ size. However, how the Fat pathway is connected to the Hippo pathway in mammals had remained poorly understood. We have shown that Fat4 is required to restrict heart growth at birth, by modulating the nuclear translocation of an adaptor protein, Amotl1, which is a partner of an effector of the Hippo pathway, Yap1.

Ragni et al., 2017 – Control of the Hippo effector Yap1 by Fat4 and Amotl1

Our research project aims at further understanding the coordination of cardiac cell behaviour and its impact on heart morphogenesis. We study the primary cilia, which mediate cell interactions by integrating a number of signalling pathways. Primary cilia are required for the formation of the heart, yet little is known about how primary cilia regulate cardiac cell behaviour.

4_cilia.png
N. Diguet – Primary cilia (red) of cardiomyocytes (green)

Our work on mouse heart morphogenesis is relevant to heart repair in humans. Heart failure is the leading cause of death in the industrialized world, owing to the limited regenerative capacity of the mammalian heart. This has been associated with the arrest of cardiomyocyte proliferation in the juvenile heart. Thus, enhancing cardiomyocyte proliferation in situ in the more mature heart, by exploiting the developmental pathways controlling heart growth, seems particularly attractive as an approach for cardiac repair. An alternative strategy is to produce cardiomyocytes from stem-cell populations. In addition to controlling the number of cardiomyocytes, it will be important to promote their oriented arrangement for producing a mature myocardium with efficient contraction.