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Developing HSCs become Notch independent by the end of maturation in the AGM region

Céline Souilhol, Javier G. Lendinez, Stanislav Rybtsov, Fiona Murphy, Heather Wilson, David Hills, Antoniana Batsivari, Anahí Binagui-Casas, Alison C. McGarvey, H. Robson MacDonald, Ryoichiro Kageyama, Christian Siebel, Suling Zhao and Alexander Medvinsky

Key Points

  • Both Notch1 and Notch2 receptors are involved in pre-HSC maturation.

  • Developing HSCs become Notch independent by the end of their maturation in the AGM region.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Abstract

The first definitive hematopoietic stem cells (dHSCs) in the mouse emerge in the dorsal aorta of the embryonic day (E) 10.5 to 11 aorta-gonad-mesonephros (AGM) region. Notch signaling is essential for early HSC development but is dispensable for the maintenance of adult bone marrow HSCs. How Notch signaling regulates HSC formation in the embryo is poorly understood. We demonstrate here that Notch signaling is active in E10.5 HSC precursors and involves both Notch1 and Notch2 receptors, but is gradually downregulated while they progress toward dHSCs at E11.5. This downregulation is accompanied by gradual functional loss of Notch dependency. Thus, as early as at final steps in the AGM region, HSCs begin acquiring the Notch independency characteristic of adult bone marrow HSCs as part of the maturation program. Our data indicate that fine stage-dependent tuning of Notch signaling may be required for the generation of definitive HSCs from pluripotent cells.

  • Submitted March 29, 2016.
  • Accepted July 5, 2016.
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