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Nat Cell Biol. 2016 Jan;18(1):7-20. doi: 10.1038/ncb3280. Epub 2015 Dec 7.

Sequential Notch activation regulates ventricular chamber development.

Author information

1
Intercellular Signalling in Cardiovascular Development &Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
2
Bioinformatics Unit, CNIC, Melchor Fernández Almagro 3, 28029 Madrid, Spain.
3
Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA.
4
Molecular Genetics of Angiogenesis Laboratory, CNIC, Melchor Fernández Almagro 3, 28029 Madrid, Spain.
5
Developmental Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA.
6
Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
7
Cardiovascular Imaging Laboratory, CNIC, Melchor Fernández Almagro 3, 28029 Madrid, Spain.
8
Instituto de Investigación Sanitaria Hospital La Princesa, 28006 Madrid, Spain.

Abstract

Ventricular chambers are essential for the rhythmic contraction and relaxation occurring in every heartbeat throughout life. Congenital abnormalities in ventricular chamber formation cause severe human heart defects. How the early trabecular meshwork of myocardial fibres forms and subsequently develops into mature chambers is poorly understood. We show that Notch signalling first connects chamber endocardium and myocardium to sustain trabeculation, and later coordinates ventricular patterning and compaction with coronary vessel development to generate the mature chamber, through a temporal sequence of ligand signalling determined by the glycosyltransferase manic fringe (MFng). Early endocardial expression of MFng promotes Dll4-Notch1 signalling, which induces trabeculation in the developing ventricle. Ventricular maturation and compaction require MFng and Dll4 downregulation in the endocardium, which allows myocardial Jag1 and Jag2 signalling to Notch1 in this tissue. Perturbation of this signalling equilibrium severely disrupts heart chamber formation. Our results open a new research avenue into the pathogenesis of cardiomyopathies.

PMID:
26641715
PMCID:
PMC4816493
DOI:
10.1038/ncb3280
[Indexed for MEDLINE]
Free PMC Article

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