Control of HSC proliferation and migration by the transcription factor EGR1

项目总结： Egr1(早期生长反应1)是即刻早期基因家族中一个著名的转录因子。 我的实验室最近发现了Egr1在调节血液活动方面的一个意想不到的有趣角色-- 形成造血干细胞(HSC)。特别是，我们广泛的初步数据表明，Egr1 正常情况下，既可以限制HSC的增殖，又可以促进HSC在BM利基中的保留。 这些发现之所以意义重大，有几个原因。首先，Egr1代表了为数不多的已知基因之一 HSC处于静止状态，这对维持HSC的功能是至关重要的。此外，Egr1代表 首次发现HSC迁移的转录调控因子，表明针对该因子可能提供新的 诱导干细胞动员用于临床移植的途径。最后，也是最值得注意的是，这个角色 单个基因同时决定HSC的增殖和解剖定位揭示了一个新的和 控制干细胞数量的潜在广泛作用机制，其中干细胞分裂是分子上的 与在利基市场的保留相协调。 因此，Egr1-/-小鼠提供了一个非同寻常的机会，可以发现对 肝星状细胞的基本特性及其临床应用通过两个聚焦和互补的 具体目的，本申请中提出的工作将(1)通过功能分析确定茎是否 细胞调节因子Bmi1是Egr1介导的HSC效应的关键靶基因 增殖和定位，(2)确定并在功能上验证Egr1的其他新靶点， 调节HSC活性；(3)阐明HSC自发动员的细胞机制(S) Egr1-/-小鼠的LT-HSC。因此，这些研究利用Egr1和Egr1-/-小鼠作为独特的模型系统 回答有关HSC功能的分子和细胞调控的长期存在的问题。

Project Summary: EGR1 (Early Growth Response 1) is a well-known transcription factor of the immediate early gene family. My lab recently discovered an unexpected and intriguing role for EGR1 in regulating the activity of blood- forming hematopoietic stem cells (HSC). In particular, our extensive Preliminary Data demonstrate that EGR1 normally functions both to limit HSC proliferation and to promote HSC retention in the BM niche. These findings are significant for several reasons. First, EGR1 represents one of only a few known regulators of HSC quiescence, which is critical in preserving HSC function. Moreover, EGR1 represents the first identified transcriptional regulator of HSC migration, suggesting that targeting this factor may provide novel avenues to inducing stem cell mobilization for clinical transplant. Finally, and most remarkably, the role of this single gene in determining both the proliferation and anatomical localization of HSC reveals a novel and potentially broadly acting mechanism for controlling stem cell number whereby stem cell division is molecularly coordinated with retention in the niche. Egr1-/- mice thus present an extraordinary opportunity for discovering new and important insights into the fundamental properties of HSC and their clinical applications. Through two focused and complementary Specific Aims, the work proposed in this application will (1) determine by functional analyses whether the stem cell regulatory factor Bmi1 represents a key target gene responsible for EGR1-mediated effects on HSC proliferation and localization, (2) identify and functionally validate additional, novel targets of EGR1 that regulate HSC activity, and (3) elucidate the cellular mechanism(s) underlying the spontaneous mobilization of LT-HSC in Egr1-/- mice. These studies thus take advantage of EGR1 and Egr1-/- mice as unique model system to answer long-standing questions about the molecular and cellular regulation of HSC function.