Hes repressors are essential regulators of hematopoietic stem cell development downstream of Notch signaling.
Hes repressors are essential regulators of hematopoietic stem cell development downstream of Notch signaling.
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DOI：
10.1084/jem.20120993
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发表时间：
2013-01-14
期刊：
影响因子：
--
通讯作者：
Bigas A
中科院分区：
文献类型：
--
作者：
Guiu J;Shimizu R;D'Altri T;Fraser ST;Hatakeyama J;Bresnick EH;Kageyama R;Dzierzak E;Yamamoto M;Espinosa L;Bigas A
通过抑制 Gata2，Hes1 是小鼠胚胎中造血干细胞发育所必需的。先前的研究已确定Notch是造血干细胞（HSC）发育的关键调节因子，但潜在的下游机制仍不清楚。 Notch 靶标 Hes1 在主动脉内皮和造血簇中广泛表达，尽管 Hes1 缺陷的小鼠没有表现出明显的造血异常。我们现在证明Hes是小鼠胚胎中HSC发育所必需的，这一功能以前未被检测到，这是Hes1突变体的主动脉/性腺/中肾（AGM）区域中Hes5从头表达的功能补偿的结果。对 Hes1 和 Hes5 缺陷胚胎的分析揭示了完整的动脉程序，过度产生非功能性造血前体细胞并且完全缺乏 HSC 活性。这些改变与造血调节因子 Runx1、c-myb 和先前确定的 Notch 靶标 Gata2 的表达增加有关。通过分析 Gata2 位点，我们鉴定了功能性 RBPJ 结合位点（该突变导致转基因胚胎中 Gata2 报告基因表达缺失）和功能性 Hes 结合位点（该突变导致造血前体细胞中 Gata2 特异性上调）。总之，我们的研究结果表明，AGM 中的 Notch 激活会触发 Gata2 和 Hes1 转录，而下一个 HES-1 蛋白会抑制 Gata2，从而创建一个限制新兴 HSC 中 Gata2 表达所需的不连贯前馈环。
Hes1 is required for the development of hematopoietic stem cells in the mouse embryo through repression of Gata2. Previous studies have identified Notch as a key regulator of hematopoietic stem cell (HSC) development, but the underlying downstream mechanisms remain unknown. The Notch target Hes1 is widely expressed in the aortic endothelium and hematopoietic clusters, though Hes1-deficient mice show no overt hematopoietic abnormalities. We now demonstrate that Hes is required for the development of HSC in the mouse embryo, a function previously undetected as the result of functional compensation by de novo expression of Hes5 in the aorta/gonad/mesonephros (AGM) region of Hes1 mutants. Analysis of embryos deficient for Hes1 and Hes5 reveals an intact arterial program with overproduction of nonfunctional hematopoietic precursors and total absence of HSC activity. These alterations were associated with increased expression of the hematopoietic regulators Runx1, c-myb, and the previously identified Notch target Gata2. By analyzing the Gata2 locus, we have identified functional RBPJ-binding sites, which mutation results in loss of Gata2 reporter expression in transgenic embryos, and functional Hes-binding sites, which mutation leads to specific Gata2 up-regulation in the hematopoietic precursors. Together, our findings show that Notch activation in the AGM triggers Gata2 and Hes1 transcription, and next HES-1 protein represses Gata2, creating an incoherent feed-forward loop required to restrict Gata2 expression in the emerging HSCs.
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影响因子：
4
作者：
Kim, Dongsan;Kwon, Yung-Keun;Cho, Kwang-Hyun
通讯作者：
Cho, Kwang-Hyun
影响因子：
56.9
作者：
Hirata, H;Yoshiura, S;Kageyama, R
通讯作者：
Kageyama, R
影响因子：
4.6
作者：
Kageyama, Ryoichiro;Ohtsuka, Toshiyuki;Kobayashi, Taeko
通讯作者：
Kobayashi, Taeko
影响因子：
20.3
作者：
Bertrand, Julien Y.;Cisson, Jennifer L.;Traver, David
通讯作者：
Traver, David
DOI：
10.1084/jem.20031556
发表时间：
2004-10-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ling KW;Ottersbach K;van Hamburg JP;Oziemlak A;Tsai FY;Orkin SH;Ploemacher R;Hendriks RW;Dzierzak E
通讯作者：
Dzierzak E