Developmental regulation of neural stem cell elimination

项目摘要 人类大脑中细胞类型的绝对数量和多样性令人震惊。了解这个细胞是如何 多样性是以这样一种方式产生和组织的，使有机体能够思考和行为是有资金的- 无关紧要。大脑中的所有神经元都是由神经干细胞产生的，神经干细胞可以自我更新 多能祖细胞。神经干细胞在调节大脑大小和细胞类型多样性方面发挥着关键作用，因为 这一群体在整个发育过程中仍然积极参与细胞周期。虽然很多努力都是为了 为了确定调控干细胞自我更新的分子机制，我对 反过来说。一旦发育，终止神经干细胞分裂的分子机制是什么？ 是完整的，这对于确保大脑回路的正确形成和抑制组织过度生长和 肿瘤发生学。除了发展，这个问题的答案对于理解时代至关重要-- 相关的认知衰退、情绪障碍和成人大脑再生能力有限。 在这里，我们使用果蝇作为一个模型系统，在其中研究终止 神经干细胞的细胞分裂，在果蝇中被称为神经母细胞。我们发现神经母细胞的一个子集， 在发育过程中被细胞死亡消除。如果死亡失败，则神经母细胞在成人体内长期存在。 并继续产生新的神经元。苍蝇提供了一个很好的模型系统来研究 调节神经干细胞清除的机制，因为大脑比哺乳动物简单得多， 有一系列复杂的遗传工具可以用来操纵基因功能，还有许多生物 过程在进化上是保守的。这项建议的目标是确定外部和内在的线索， 使用遗传和细胞生物学方法调节神经干细胞的消除。第一个目标是测试 假设成鞘神经胶质细胞提供神经母细胞存活所必需的营养支持。第二个目标 研究神经母细胞在通过细胞死亡消除之前是否进入自噬，这可能起到 一种有效的后备机制，以确保终止神经母细胞的增殖。此外，我们还将开展一项 无偏正向基因筛查，以确定神经母细胞消除所需的基因。最后，我们建议 将我们的工作过渡到哺乳动物模型系统，这将为理解人类提供更多的洞察力 疾病。另一个长期目标是利用果蝇作为识别神经所需基因的手段 消除干细胞，然后测试哺乳动物的同源基因是否具有这一共同功能。 在遗传学和癌症生物学专家Iswar Hariharan博士的指导下，在 由Arturo Alvarez-Buylla博士、David Schaffer博士和Andy Wurmser博士指导，他们都是哺乳动物专家 神经干细胞和神经发生，候选人将获得基因筛查方面的专业知识，使用哺乳动物 模型系统和哺乳动物神经干细胞生物学。这项研究和培训计划将为她提供 一个很好的基础，可以过渡到一个独立的研究岗位。

Project Summary The sheer number and diversity of cell types within the human brain is staggering. Understanding how this cell diversity is generated and organized in such a way that allows organisms to think and behave is of fund- amental importance. All neurons within the brain are generated from neural stem cells, which are self-renewing multi-potent progenitors. Neural stem cells play a key role in regulating brain size and cell type diversity, since this population remains actively engaged in the cell cycle throughout development. While much effort is aimed towards identifying the molecular mechanisms regulating stem cell self-renewal, I have become fascinated by the converse. What are the molecular mechanisms that terminate neural stem cell divisions once development is complete, which is essential to ensure proper formation of brain circuitry and to inhibit tissue overgrowth and tumorigenesis. Beyond development, the answer to this question is of key importance for under-standing age- related cognitive declines, mood disorders, and limited regenerative capacity of adult brains. Here we use Drosophila as a model system in which to investigate the mechanisms that terminate the cell divisions of neural stem cells, known as neuroblasts in Drosophila. We find that a subset of neuroblasts, are eliminated during development by cell death. If death fails, then neuroblasts persist long term in the adult brain and continue generating new neurons. Flies provide an excellent model system for studying the mechanisms regulating neural stem cell elimination, because the brain is vastly less complex than mammals, there exists a range of sophisticated genetic tools for manipulating gene function, and many biological processes are evolutionarily conserved. The goal of this proposal is to identify extrinsic and intrinsic cues that regulate neural stem cell elimination using a genetic and cell biological approach. The first aim tests the hypothesis that ensheathig glia provide trophic support necessary for neuroblast survival. The second aim investigates whether neuroblasts enter autophagy, prior to their elimination via cell death, which may serve as a potent backup mechanism to ensure termination of neuroblast proliferation. In addition, we will carry out an unbiased forward genetic screen to identify genes required for neuroblast elimination. Finally, we propose to transition our work to a mammalian model system, which will provide greater insight into understanding human disease. One more long-term goal is to use Drosophila as a means for identifying genes required for neural stem cell elimination, and then test whether the mammalian orthologues share this common function. Under the mentorship of Dr. Iswar Hariharan, an expert in genetics and cancer biology, and under the guidance of Dr. Arturo Alvarez-Buylla, Dr. David Schaffer, and Dr. Andy Wurmser, all experts in mammalian neural stem cells and neurogenesis, the candidate will gain expertise in genetic screening, using mammalian model systems, and mammalian neural stem cell biology. This research and training plan will provide her with an excellent foundation with which to transition to an independent research position.