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

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。了解这种巨大多样性的神经元类型是如何产生和组织的 允许我们和其他成年动物执行如此庞大的复杂任务和行为是非常重要的 重要性。到目前为止，我们成人大脑中的大多数神经元都是在发育过程中产生的，要么直接产生，要么 间接地来自固定但相当不同的神经干细胞群体的细胞分裂。 神经干细胞因其位置和神经干细胞本身的不同而存在分子差异 会随着时间的推移改变它们固有的遗传程序。这项提案中概述的研究旨在 更好地理解神经干细胞外在因子与神经干细胞内在因子如何结合 控制发育过程中通过时间和空间产生的神经元的数量和类型。 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 揭示调控神经干细胞增殖决定的遗传途径和分子机制， 从静止到增殖，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 决定。在果蝇中，不同的神经干细胞对食物营养供应的反应是不同的。多数 以饮食营养和PI3依赖的方式进入和退出静止状态，但有一小部分除外。 神经干细胞是神经干细胞，它不依赖于食物中营养物质的供应而持续分裂。 产生对记忆和学习非常重要的神经元的细胞。通过基因和单细胞测序 技术，我们正在努力识别这些神经干细胞类型之间的内在差异 区分营养依赖和营养独立。我们还在努力确定如何 在发育过程中消耗的饮食营养调节神经干细胞的时间程序，从而调节类型 以及产生的神经元数量。果蝇的神经干细胞顺序表达一系列 随时间推移的转录因子，指定在每个细胞分裂时产生的神经元类型。是否为外在的 影响神经母细胞内在时间程序的因素，如营养物质的可获得性，目前尚不清楚。 最后，我们还致力于绘制出调节神经干细胞增殖的神经回路。 根据膳食营养素的可获得性作出决定。总之，这里概述的研究将推动我们的 了解神经干细胞发育过程中的增殖控制以及膳食营养的有效性 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发现 在正常发育和疾病状态下的翻译干细胞研究。

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 cell 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 affects 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.