期刊
GENES & DEVELOPMENT
卷 28, 期 6, 页码 576-593出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.227496.113
关键词
Notch; hematopoietic stem cell; transcriptional activation domain
资金
- Leukemia and Lymphoma Society Fellow Award [T32HL007843]
- Financial Peace University fellowship [AP2008-01883]
- National Marfan Foundation Award
- Burroughs Wellcome Fund [K08 HL107449]
- National Institutes of Health [R01AI047833, P01CA119070, U01HL100405]
- Spanish government [PLE09-0111, SAF2010-15450]
- Red Tematica de Investigacion Cooperativa en Cancer [RD12/0036/0054]
- [T32CA009140]
- [T32GM007229]
Notch1 is required to generate the earliest embryonic hematopoietic stem cells (HSCs); however since Notch-deficient embryos die early in gestation, additional functions for Notch in embryonic HSC biology have not been described. We used two complementary genetic models to address this important biological question. Unlike Notch1-deficient mice, mice lacking the conserved Notch1 transcriptional activation domain (TAD) show attenuated Notch1 function in vivo and survive until late gestation, succumbing to multiple cardiac abnormalities. Notch1 TAD-deficient HSCs emerge and successfully migrate to the fetal liver but are decreased in frequency by embryonic day 14.5. In addition, TAD-deficient fetal liver HSCs fail to compete with wild-type HSCs in bone marrow transplant experiments. This phenotype is independently recapitulated by conditional knockout of Rbpj, a core Notch pathway component. In vitro analysis of Notch1 TAD-deficient cells shows that the Notch1 TAD is important to properly assemble the Notch1/Rbpj/Maml trimolecular transcription complex. Together, these studies reveal an essential role for the Notch1 TAD in fetal development and identify important cell-autonomous functions for Notch1 signaling in fetal HSC homeostasis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据