Regulation of Shh Signaling by Cellular Energetics

项目总结： Shh途径在发育、干细胞维持和组织动态平衡中起着关键作用。 小脑发育过程中失控的Shh信号导致髓母细胞瘤，这是最常见的 儿童期儿童脑瘤，推测起源于颗粒细胞前体细胞。在.期间 出生后，GCP在外部颗粒层经历了快速和短暂的增殖 (EGL)在分化和向内迁移成为颗粒神经元之前对Shh信号做出反应。 持续的Shh信号对抗这种刻板的发育模式，导致分化中断 GCPs长时间停留在被认为是小脑肿瘤起源的外侧EGL。因此， 阐明Cgp增殖和分化的调控机制对我们的 对小脑肿瘤发生的认识。放松管制的细胞生长和增殖是 需要耗费能量的合成代谢过程的肿瘤，如蛋白质合成和脂肪生成。这些 合成代谢过程受到细胞能量传感器的高度调控和严格控制。钥匙 在能量耗竭条件下被激活的能量感受器是AMP激活的蛋白激酶(AMPK)。 我们发现AMPK是GCPs和原代髓母细胞瘤细胞Shh信号的有效抑制因子。 此外，AMPK被选择性地激活在发育中的小脑的内侧EGL，Shh信号是在那里 监管下调和GCP已经开始分化。这些观察结果表明，AMPK可能在 在GCP中调节Shh信号在分化、增殖和肿瘤发生中的关键作用。我们将测试 这一假说有三个目的：1)阐明AMPK激活拮抗Shh的机制 2)确定AMPK在体内调节GCP增殖和分化中的作用；3) 检测AMPK在Shh诱导的髓母细胞瘤中的激活作用。

Project Summary: The Shh pathway plays critical roles in development, stem cell maintenance and tissue homeostasis. Deregulated Shh signaling during cerebellar development causes medulloblastoma, the most common pediatric brain tumors in childhood with presumed cellular origin in granule cell precursors (GCPs). During postnatal development, GCPs undergo rapid and transient proliferation in the outer external granule layer (EGL) in response to Shh signaling before differentiating and migrating inward to become granule neurons. Persistent Shh signaling counters this stereotypic developmental pattern, resulting in disrupted differentiation and prolonged stay of GCPs in the outer EGL where cerebellar neoplasm is thought to initiate. Therefore, elucidating the mechanism by which CGP proliferation and differentiation are regulated is important to our understanding of cerebellar tumorigenesis. Deregulated cellular growth and proliferation are hallmarks of neoplasms that entail energy-consuming anabolic processes such as protein synthesis and lipogenesis. These anabolic processes are highly regulated and subject to stringent control by cellular energy sensors. The key energy sensor that is activated under condition of energy depletion is AMP-activated protein kinase (AMPK). We discovered that AMPK is a potent inhibitor of Shh signaling in GCPs and primary medulloblastoma cells. Moreover, AMPK is selectively activated in the inner EGL of the developing cerebellum where Shh signaling is downregulated and GCPs have begun differentiating. These observations suggest that AMPK may play a critical role in modulating Shh signaling in GCPs for differentiation, proliferation and tumorigenesis. We will test this hypothesis by three aims: 1) Elucidate the mechanism by which AMPK activation antagonizes Shh pathway activity; 2) Determine the role of AMPK in modulating GCP proliferation and differentiation in vivo; 3) Determine the effect of AMPK activation in Shh-driven medulloblastoma in vivo.