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

项目概要/摘要： 我们的大脑是由各种各样的神经元组成的，这些神经元在分子上，形态上， 功能不同。了解神经元类型的巨大多样性是如何产生的， 让我们和其他成年动物能够完成如此复杂的任务， 行为非常重要。到目前为止，我们成年人大脑中的大多数神经元都是在 发展，直接或间接从细胞分裂的定义，但相当异质 神经干细胞神经干细胞之间存在分子差异， 位置和神经干细胞本身可以随着时间的推移改变其内在的遗传程序。 这项提案中概述的研究旨在更好地了解神经干细胞如何 外源性因子与神经干细胞内源性因子共同调控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，我们使用遗传学上易于处理的模式生物，黑腹果蝇， 揭示调节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，然后一旦发展完成就终止。我们 研究目标包括更好地了解膳食营养素的可利用性如何影响神经系统。 干细胞增殖的决定。在果蝇中，不同的神经干细胞对饮食的反应不同。 养分有效性大多数进入和退出静止在饮食营养和PI3激酶依赖 除了一小部分人之外，神经干细胞不依赖于饮食而持续分裂 营养物质是神经干细胞，它们产生对记忆和学习很重要的神经元。 通过基因和单细胞测序技术，我们正在努力确定内在的 这些神经干细胞类型之间的差异，区分营养依赖与营养， 独立我们还在研究在怀孕期间饮食中的营养物质是如何消耗的。 发育调节神经干细胞时间程序，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 它指定了每次细胞分裂时产生的神经元类型。是否有外在因素，如营养素 可用性，影响神经母细胞内在的时间程序是目前未知的。最后，我们还 致力于绘制出调节神经干细胞增殖决定的神经回路， 对膳食营养素有效性的反应。总之，这里概述的研究将推动我们的 了解发育过程中神经干细胞增殖的控制以及饮食营养 可用性影响产生的神经元的类型和数量。这些见解应该激发新的 在正常发育和疾病状态下的转化干细胞研究中的发现。

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.