TY - JOUR
T1 - Developing HSCs become Notch independent by the end of maturation in the AGM region
AU - Souilhol, Céline
AU - Gonzalez Lendinez, Javier
AU - Rybtsov, Stanislav
AU - Murphy, Fiona
AU - Wilson, Heather
AU - Hills, David
AU - Batsivari, Antoniana
AU - Binagui-Casas, Anahi
AU - McGarvey, Alison
AU - MacDonald, H. Robson
AU - Kageyama, Ryoichiro
AU - Siebel, Christian
AU - Zhao, Suling
AU - Medvinsky, Alexander
N1 - This work was supported by Wellcome Trust, the People Programme (Marie Curie
Actions) of the European Union’ Seventh Framework Programme FP7, LLR/ Bloodwise, BBSRC, MRC.
PY - 2016/9/22
Y1 - 2016/9/22
N2 - The first definitive haematopoietic stem cells (dHSCs) in the mouse emerge in the dorsal aorta of the embryonic day (E)10.5-11 aorta-gonad-mesonephros (AGM) region. Notch signalling is essential for early HSC development but is dispensable for the maintenance of adult bone marrow HSCs. How Notch signalling regulates HSCs formation in the embryo is poorly understood. We demonstrate here that Notch signalling is active in E10.5 HSC precursors and involves both Notch1 and Notch2 receptors, but is gradually down-regulated while they progress towards dHSCs at E11.5. This down-regulation 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 programme. Our data indicate that fine stagedependent tuning of Notch signalling may be required for the generation of definitive HSCs from pluripotent cells.
AB - The first definitive haematopoietic stem cells (dHSCs) in the mouse emerge in the dorsal aorta of the embryonic day (E)10.5-11 aorta-gonad-mesonephros (AGM) region. Notch signalling is essential for early HSC development but is dispensable for the maintenance of adult bone marrow HSCs. How Notch signalling regulates HSCs formation in the embryo is poorly understood. We demonstrate here that Notch signalling is active in E10.5 HSC precursors and involves both Notch1 and Notch2 receptors, but is gradually down-regulated while they progress towards dHSCs at E11.5. This down-regulation 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 programme. Our data indicate that fine stagedependent tuning of Notch signalling may be required for the generation of definitive HSCs from pluripotent cells.
KW - HSC
KW - embryo
KW - Notch pathway
KW - Hes1
U2 - 10.1182/blood-2016-03-708164
DO - 10.1182/blood-2016-03-708164
M3 - Article
SN - 0006-4971
VL - 128
SP - 1567
EP - 1157
JO - Blood
JF - Blood
IS - 12
ER -