TY - JOUR
T1 - Notch signal strength controls cell fate in the haemogenic endothelium
AU - Gama-Norton, Leonor
AU - Ferrando, Eva
AU - Ruiz-Herguido, Cristina
AU - Liu, Zenhy
AU - Guiu, Jordi
AU - Islam, Abul B.M.M.K.
AU - Lee, Sung Uk
AU - Yan, Minhong
AU - Guidos, Cynthia J.
AU - López-Bigas, Nuria
AU - Maeda, Takahiro
AU - Espinosa, Lluis
AU - Kopan, Raphael
AU - Bigas, Anna
N1 - Funding Information:
L.G.-N. was a recipient of Marie Curie Intra-European Fellowship (PIEF-GA-2011-302226). E.F. and J.G. are recipients of FPI (BES-2011-048360 and BES-2008-005708, respectively). This research was funded by the Ministerio de Economía y Competitividad (PLE2009-0111, SAF2010-15450, SAF2013-40922-R), Red Temática de Investigación Cooperativa en Cáncer (RTICC) (RD12/0036/0054), Agència de Gestió d’Ajuds Universitaris i de Recerca (AGAUR; 2014SGR-124) to A.B.
PY - 2015/10/14
Y1 - 2015/10/14
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms9510
DO - 10.1038/ncomms9510
M3 - Article
C2 - 26465397
AN - SCOPUS:84944404730
VL - 6
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 8510
ER -