Notch signal strength controls cell fate in the haemogenic endothelium

Leonor Gama-Norton; Eva Ferrando; Cristina Ruiz-Herguido; Zenhy Liu; Jordi Guiu; Abul B.M.M.K. Islam; Sung Uk Lee; Minhong Yan; Cynthia J. Guidos; Nuria López-Bigas; Takahiro Maeda; Lluis Espinosa; Raphael Kopan; Anna Bigas

doi:10.1038/ncomms9510

Notch signal strength controls cell fate in the haemogenic endothelium

Leonor Gama-Norton, Eva Ferrando, Cristina Ruiz-Herguido, Zenhy Liu, Jordi Guiu, Abul B.M.M.K. Islam, Sung Uk Lee, Minhong Yan, Cynthia J. Guidos, Nuria López-Bigas, Takahiro Maeda, Lluis Espinosa, Raphael Kopan, Anna Bigas^*

^*Corresponding author for this work

77 Citations (Scopus)

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.

Original language	English
Article number	8510
Journal	Nature Communications
Volume	6
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms9510
Publication status	Published - 14 Oct 2015
Externally published	Yes

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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.",

author = "Leonor Gama-Norton and Eva Ferrando and Cristina Ruiz-Herguido and Zenhy Liu and Jordi Guiu and Islam, {Abul B.M.M.K.} and Lee, {Sung Uk} and Minhong Yan and Guidos, {Cynthia J.} and Nuria L{\'o}pez-Bigas and Takahiro Maeda and Lluis Espinosa and Raphael Kopan and Anna Bigas",

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doi = "10.1038/ncomms9510",

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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

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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DO - 10.1038/ncomms9510

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SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

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ER -

Notch signal strength controls cell fate in the haemogenic endothelium

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