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是惊人的。了解这个细胞 多样性的产生和组织方式使生物体能够思考和行为， 情感的重要性大脑中的所有神经元都是由神经干细胞产生的，神经干细胞是自我更新的。 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， 该群体在整个发育过程中保持活跃地参与细胞周期。虽然许多努力旨在 为了确定调节干细胞自我更新的分子机制，我对以下内容着迷： 匡威亦然。神经干细胞一旦发育就终止分裂的分子机制是什么 是完整的，这是必要的，以确保适当的形成脑电路和抑制组织过度生长， 肿瘤发生除了发展，这个问题的答案对于理解年龄至关重要- 相关的认知能力下降，情绪障碍，以及成年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，在其中调查的机制，终止 神经干细胞的细胞分裂，在果蝇中被称为成神经细胞。我们发现一部分神经母细胞， 在发育过程中通过细胞死亡被消除。如果死亡失败，则成神经细胞在成人中长期存在 大脑并继续产生新的神经元。苍蝇提供了一个很好的模型系统， 调节神经干细胞消除的机制，因为大脑远不如哺乳动物复杂， 存在一系列用于操纵基因功能的复杂遗传工具， 进化过程是保守的。这个建议的目标是识别外在和内在的线索， 使用遗传和细胞生物学方法调节神经干细胞消除。第一个目标是测试 假设鞘内胶质细胞为成神经细胞存活提供必要营养支持。第二个目的 研究神经母细胞是否进入自噬，在它们通过细胞死亡消除之前，这可能作为 一种有效的后备机制，以确保终止神经母细胞增殖。此外，我们会进行一项 无偏正向遗传筛选，以鉴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深入的见解。 疾病另一个长期目标是利用果蝇作为一种手段，以确定所需的基因，神经 干细胞消除，然后测试哺乳动物直系同源物是否具有这种共同功能。 在遗传学和癌症生物学专家Iswar Hariharan博士的指导下， Arturo Alvarez-Buylla博士、大卫谢弗博士和安迪·沃姆瑟博士的指导，他们都是哺乳动物领域的专家。 神经干细胞和神经发生，候选人将获得遗传筛选的专业知识，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，过渡到一个独立的研究职位。

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.