Control of HSC proliferation and migration by the transcription factor EGR1

项目摘要： EGR 1（Early Growth Response 1）是一种已知的即刻早期基因家族转录因子。 我的实验室最近发现了一个意想不到的和有趣的作用EGR 1在调节血液的活动- 形成造血干细胞（HSC）。特别是，我们广泛的初步数据表明，EGR 1 通常具有限制HSC增殖和促进HSC保留在BM龛中的功能。 这些发现具有重要意义，原因有几个。首先，EGR 1代表了已知的为数不多的 HSC静止的调节因子，这对于保持HSC功能至关重要。此外，EGR 1代表 首次鉴定了HSC迁移的转录调节因子，这表明靶向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， 单基因在决定HSC增殖和解剖定位中的作用揭示了一种新的， 一种潜在的广泛作用机制，用于控制干细胞数量，从而使干细胞分裂在分子上 与在壁龛中的保留相协调。 因此，Egr 1-/-小鼠为发现新的重要见解提供了一个非凡的机会。 HSC的基本特性及其临床应用。通过两个重点和互补 具体目的，本申请中提出的工作将（1）通过功能分析确定股骨柄是否 细胞调节因子Bmi 1是EGR 1介导HSC作用的关键靶基因 增殖和定位，（2）鉴定和功能验证额外的，新的EGFR 1靶点， 调节HSC活性，和（3）阐明HSC自发动员的细胞机制。 Egr 1-/-小鼠中的LT-HSC。因此，这些研究利用EGR 1和Egr 1-/-小鼠作为独特的模型系统 回答长期存在的关于HSC功能的分子和细胞调节的问题。

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.