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Nat Commun. 2015 Oct 14;6:8510. doi: 10.1038/ncomms9510.

Notch signal strength controls cell fate in the haemogenic endothelium.

Author information

1
Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona 08003, Spain.
2
Division of Developmental Biology, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio 45229-3026, USA.
3
Research Unit on Biomedical Informatics, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona 08003, Spain.
4
Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka 1000, Bangladesh.
5
Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
6
Department of Molecular Biology, Genentech, South San Francisco, California 94080, USA.
7
Program in Developmental and Stem Cell Biology, Department of Immunology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada M5G 0A4.
8
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain.

Abstract

Acquisition of the arterial and haemogenic endothelium fates concurrently occur in the aorta-gonad-mesonephros (AGM) region prior to haematopoietic stem cell (HSC) generation. The arterial programme depends on Dll4 and the haemogenic endothelium/HSC on Jag1-mediated Notch1 signalling. How Notch1 distinguishes and executes these different programmes in response to particular ligands is poorly understood. By using two Notch1 activation trap mouse models with different sensitivity, here we show that arterial endothelial cells and HSCs originate from distinct precursors, characterized by different Notch1 signal strengths. Microarray analysis on AGM subpopulations demonstrates that the Jag1 ligand stimulates low Notch strength, inhibits the endothelial programme and is permissive for HSC specification. In the absence of Jag1, endothelial cells experience high Dll4-induced Notch activity and select the endothelial programme, thus precluding HSC formation. Interference with the Dll4 signal by ligand-specific blocking antibodies is sufficient to inhibit the endothelial programme and favour specification of the haematopoietic lineage.

PMID:
26465397
PMCID:
PMC4634136
DOI:
10.1038/ncomms9510
[Indexed for MEDLINE]
Free PMC Article

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