Notch and Bmp signaling pathways act coordinately during the formation of the proepicardium

Laura Andrés-Delgado; María Galardi-Castilla; Juliane Münch; Marina Peralta; Alexander Ernst; Juan Manuel González-Rosa; Federico Tessadori; Luis Santamaría; Jeroen Bakkers; Julien Vermot; José Luis de la Pompa; Nadia Mercader

doi:10.1002/dvdy.229

Notch and Bmp signaling pathways act coordinately during the formation of the proepicardium

Dev Dyn. 2020 Dec;249(12):1455-1469. doi: 10.1002/dvdy.229. Epub 2020 Sep 3.

Authors

Laura Andrés-Delgado^{1

2}, María Galardi-Castilla¹, Juliane Münch^{3

4

5}, Marina Peralta^{1

6

7}, Alexander Ernst⁸, Juan Manuel González-Rosa⁹, Federico Tessadori¹⁰, Luis Santamaría², Jeroen Bakkers^{10

11}, Julien Vermot^{6

12}, José Luis de la Pompa^{3

4}, Nadia Mercader^{1

8}

Affiliations

¹ Development of the Epicardium and its Role During Regeneration Laboratory, National Center of Cardiovascular Research Carlos III, Madrid, Spain.
² Department of Anatomy, Histology, and Neuroscience, School of Medicine, Autonoma University of Madrid, Madrid, Spain.
³ Intercellular Signaling in Cardiovascular Development and Disease Laboratory, National Center of Cardiovascular Research Carlos III, Madrid, Spain.
⁴ Ciber CV, Madrid, Spain.
⁵ Institute of Biochemistry and Biology, Potsdam University, Potsdam, Germany.
⁶ Institute of Genetics and Molecular and Cellular Biology (IGBMC), Illkirch, France.
⁷ Australian Regenerative Institute, Monash University, Clayton, Victoria, Australia.
⁸ Institute of Anatomy, University of Bern, Bern, Switzerland.
⁹ Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹⁰ Hubrecht Institute-KNAW and UMC Utrecht, Utrecht, The Netherlands.
¹¹ Division of Heart and Lungs, Department of Medical Physiology, University Medical Center Utrecht, The Netherlands.
¹² Department of Bioengineering, Imperial College London, London, UK.

Abstract
in English, German

Background: The epicardium is the outer mesothelial layer of the heart. It encloses the myocardium and plays key roles in heart development and regeneration. It derives from the proepicardium (PE), cell clusters that appear in the dorsal pericardium (DP) close to the atrioventricular canal and the venous pole of the heart, and are released into the pericardial cavity. PE cells are advected around the beating heart until they attach to the myocardium. Bmp and Notch signaling influence PE formation, but it is unclear how both signaling pathways interact during this process in the zebrafish.

Results: Here, we show that the developing PE is influenced by Notch signaling derived from the endothelium. Overexpression of the intracellular receptor of notch in the endothelium enhances bmp expression, increases the number of pSmad1/5 positive cells in the DP and PE, and enhances PE formation. On the contrary, pharmacological inhibition of Notch1 impairs PE formation. bmp2b overexpression can rescue loss of PE formation in the presence of a Notch1 inhibitor, but Notch gain-of-function could not recover PE formation in the absence of Bmp signaling.

Conclusions: Endothelial Notch signaling activates bmp expression in the heart tube, which in turn induces PE cluster formation from the DP layer.

Notch is active on endothelial cells but not on EPDCs cells during PE formation.
Endothelial Notch signaling activates Bmp expression in the heart‐tube.
Notch and Bmp pathways induce PE cluster formation from the DP layer.

Keywords: heart development; pericardium; zebrafish.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Morphogenetic Proteins / metabolism*
Cell Differentiation / physiology
Heart / embryology*
Organogenesis / physiology*
Pericardium / embryology*
Pericardium / metabolism
Receptors, Notch / metabolism*
Signal Transduction / physiology*
Zebrafish

Substances

Bone Morphogenetic Proteins
Receptors, Notch

Abstract in English, German

Publication types

MeSH terms

Substances

Grants and funding

Abstract
in English, German