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Notch signal strength controls cell fate in the haemogenic endothelium

Author

Listed:
  • Leonor Gama-Norton

    (Program in Cancer Research, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM))

  • Eva Ferrando

    (Program in Cancer Research, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM))

  • Cristina Ruiz-Herguido

    (Program in Cancer Research, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM))

  • Zhenyi Liu

    (University of Cincinnati)

  • Jordi Guiu

    (Program in Cancer Research, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM))

  • Abul B. M. M. K. Islam

    (Research Unit on Biomedical Informatics, Universitat Pompeu Fabra
    University of Dhaka)

  • Sung-Uk Lee

    (Harvard Medical School, Brigham and Women's Hospital)

  • Minhong Yan

    (Genentech)

  • Cynthia J. Guidos

    (Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute)

  • Nuria López-Bigas

    (Research Unit on Biomedical Informatics, Universitat Pompeu Fabra
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

  • Takahiro Maeda

    (Harvard Medical School, Brigham and Women's Hospital)

  • Lluis Espinosa

    (Program in Cancer Research, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM))

  • Raphael Kopan

    (University of Cincinnati)

  • Anna Bigas

    (Program in Cancer Research, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM))

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.

Suggested Citation

  • Leonor Gama-Norton & Eva Ferrando & Cristina Ruiz-Herguido & Zhenyi Liu & Jordi Guiu & Abul B. M. M. K. Islam & Sung-Uk Lee & Minhong Yan & Cynthia J. Guidos & Nuria López-Bigas & Takahiro Maeda & Llu, 2015. "Notch signal strength controls cell fate in the haemogenic endothelium," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9510
    DOI: 10.1038/ncomms9510
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    Cited by:

    1. Brandon Hadland & Barbara Varnum-Finney & Stacey Dozono & Tessa Dignum & Cynthia Nourigat-McKay & Adam M. Heck & Takashi Ishida & Dana L. Jackson & Tomer Itkin & Jason M. Butler & Shahin Rafii & Cole , 2022. "Engineering a niche supporting hematopoietic stem cell development using integrated single-cell transcriptomics," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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