title: Notch signal strength controls cell fate in the haemogenic endothelium.
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.
authors.affiliation: Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona 08003, Spain.
authors.forename: Leonor
authors.initials: L
authors.lastname: Gama-Norton
authors.affiliation: Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona 08003, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Ferrando
authors.affiliation: Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona 08003, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ruiz-Herguido
authors.forename: Zhenyi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Division of Developmental Biology, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio 45229-3026, USA.
authors.forename: Zenhy
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona 08003, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Guiu
authors.affiliation: Research Unit on Biomedical Informatics, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona 08003, Spain.|Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka 1000, Bangladesh.
authors.forename: Abul B M M K
authors.initials: AB
authors.lastname: Islam
authors.affiliation: Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Sung-Uk
authors.initials: SU
authors.lastname: Lee
authors.affiliation: Department of Molecular Biology, Genentech, South San Francisco, California 94080, USA.
authors.forename: Minhong
authors.initials: M
authors.lastname: Yan
authors.affiliation: Program in Developmental and Stem Cell Biology, Department of Immunology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada M5G 0A4.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Guidos
authors.affiliation: Research Unit on Biomedical Informatics, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona 08003, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: López-Bigas
authors.affiliation: Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona 08003, Spain.
authors.forename: Lluis
authors.initials: L
authors.lastname: Espinosa
authors.affiliation: Division of Developmental Biology, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio 45229-3026, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Kopan
authors.affiliation: Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona 08003, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Bigas
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001011:Aorta / Q000196:embryology; D001158:Arteries / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000196:embryology / Q000378:metabolism*; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins