Nutrient-dependent regulation of neural stem cell proliferation and neural circuit formation

项目摘要/摘要： 我们的大脑是由各种各样的神经元组成的，这些神经元在分子、形态和 在功能上截然不同。了解这种巨大的神经元类型多样性是如何产生的 有组织地允许我们和其他成年动物执行如此广泛的复杂任务和 行为是非常重要的。到目前为止，我们成人大脑中的大多数神经元是在 发育，无论是直接还是间接从细胞分裂中确定的但相当异质的 神经干细胞群体。神经干细胞之间存在分子差异，基于它们的 随着时间的推移，位置和神经干细胞本身可以改变其固有的遗传程序。 这项提案中概述的研究旨在更好地理解神经干细胞如何 外在因素与神经干细胞内在因素相结合控制神经元的数量和类型 在发展过程中通过时间和空间产生的。 在Siegrist实验室，我们使用遗传上易驯化的模式生物--黑腹果蝇，来 揭示神经干细胞增殖的遗传途径和分子机制 决定，从静止到扩散，然后一旦发育完成就终止。我们的 研究目标包括更好地了解膳食营养素供应如何影响神经 干细胞增殖决策。在果蝇中，不同的神经干细胞对饮食的反应不同 养分可利用性。大多数人在饮食营养和PI3依赖的情况下进入和退出静止状态 方式，除了一个很小的子集。与饮食无关的持续分裂的神经干细胞 营养可获得性是指神经干细胞产生对记忆和学习至关重要的神经元。 通过遗传和单细胞测序技术，我们正在努力识别内在的 这些神经干细胞类型之间的差异区分了营养依赖和营养- 独立。我们还在努力确定在饮食过程中如何摄入营养素 发育调节神经干细胞的时间程序，从而调节神经元的类型和数量 制作。果蝇的神经干细胞随着时间的推移顺序表达一系列转录因子 它规定了每个细胞分裂时产生的神经元类型。是否存在营养等外在因素 可获得性，影响神经母细胞固有的时间程序目前尚不清楚。最后，我们也是 致力于绘制出调节神经干细胞增殖决定的神经回路 对膳食营养素供应的反应。总之，这里概述的研究将推动我们的 对发育过程中神经干细胞增殖控制及膳食营养的认识 可获得性影响所产生的神经元的类型和数量。这些洞察力应该会刺激新的 在正常发育和疾病状态下的翻译干细胞研究方面的发现。

Project Summary/Abstract: Our brain is composed of an immense diversity of neurons that are molecularly, morphologically, and functionally distinct. Understanding how this immense diversity of neuron types is generated and organized to allow us and other adult animals to carry out such a vast array of complex tasks and behaviors is of great importance. By far, most of the neurons in our adult brains are generated during development, either directly or indirectly from the cell divisions of a defined but rather heterogeneous population of neural stem cells. Molecular differences exist among neural stem cells based on their location and neural stem cells themselves can change their intrinsic genetic programs over time. Research outlined in this proposal is geared towards better understanding of how neural stem cell extrinsic factors integrate with neural stem cell intrinsic factors to control numbers and types of neurons produced through time and space during development. In the Siegrist lab, we use the genetically tractable model organism, Drosophila melanogaster, to uncover the genetic pathways and molecular mechanisms regulating neural stem cell proliferation decisions, from quiescence to proliferation, and then termination once development is complete. Our research goals include gaining a better understanding of how dietary nutrient availability affects neural stem cell proliferation decisions. In Drosophila, different neural stem cells respond differently to dietary nutrient availability. Most enter and exit quiescence in a dietary nutrient- and PI3-kinase-dependent manner, except for a small subset. The neural stem cells that divide continuously independent of dietary nutrient availability are the neural stem cells that generate neurons important for memory and learning. Through genetic and single cell sequencing techniques, we are working to identify the intrinsic differences among these neural stem cell types that distinguish nutrient-dependence versus nutrient- independence. We are also working on determining how dietary nutrients consumed during development regulate neural stem cell temporal programs and thus types and numbers of neurons produced. Neural stem cells in Drosophila sequentially express a series of transcription factors over time that specify the neuron types produced at each cell division. Whether extrinsic factors, such as nutrient availability, affect neuroblast intrinsic temporal programs is currently unknown. Finally, we are also working to map out the neural circuitry that regulates neural stem cell proliferation decisions in response to dietary nutrient availability. Altogether, the research outlined here will advance our understanding of neural stem cell proliferation control during development and how dietary nutrient availability affects types and numbers of neurons produced. These insights should stimulate new discoveries in translational stem cell research in the context of normal development and disease states.