Cell Fate Specification in the Developing Nervous System

基本螺旋-环-螺旋类的原神经转录因子在指定 神经前体细胞的群体及其后代的分化的控制。了解 这些因子的多重、质的不同功能是发育神经科学的中心目标。这个 这项研究的长期目标是在分子遗传水平上定义 线虫原神经基因Lin-32控制从单个细胞产生三种不同类型的神经细胞 神经前体细胞。这三种细胞类型(称为RNA和RnB的两个神经元和一个神经胶质样结构细胞， RNST)共同形成射线感受器，这是线虫雄性尾巴中的一个模型感觉器官。我们假设 射线前体细胞的后代由转录级联来组合指定，该转录级联 取决于LIN-32和它所在的蜂窝环境。这里提出的研究将 确定并从功能上描述建立这一背景的因素以及那些执行 特定的射线细胞命运。在其他特征中，线虫的遗传复杂性和 在活体动物中观察发育和标记基因表达使线虫成为理想的线虫模型 解决这些问题。这项提议概述了三个相关的目标，通过表征来检验我们的假设 协调射线发展的监管网络。(1)我们将测试监管的新模式 LIN-32的不对称表达模式射线细胞命运在射线亚系中的一个分支，并探讨其作用 Wnt/MAPK信号在这一过程中的作用。(2)我们将研究LIM-HD基因LIM-7在 RnB神经元亚型的规范及其与LIN-32的关系。(3)我们要写一部小说 正向遗传筛选和分子克隆两个新基因，它们控制射线中的神经模式 亚等级制度。这些研究将确定决定神经原发炎特异性的遗传机制 基因功能和神经亚型的建立在一个简单易处理的模型中。理解 这些机制对于充分认识人类神经发育疾病和 理性疗法的设计。 LAY摘要：使用一种小型土壤蛔虫，我们将探索产生细胞的遗传机制 神经系统的复杂性。这对人类疾病具有特别的相关性，在这些疾病中，这些过程 都被打乱了。

Proneural transcription factors of the basic helix-loop-helix class have critical, conserved roles in specifying populations of neural precursor cells and in controlling the differentiation of their progeny. Understanding the multiple, qualitatively different functions of these factors is a central goal in developmental neuroscience. The long-term goal of this research is to define at a molecular genetic level the mechanisms by which the C. elegans proneural gene lin-32 controls the generation of three distinct neural cell types from a single neural precursor cell. These three cell types (two neurons called RnA and RnB and a glial-like structural cell, Rnst) together form the ray sensillum, a model sensory organ in the C. elegans male tail. We hypothesize that the progeny of the ray precursor cell are specified combinatorially by a transcriptional cascade that depends both on lin-32 and on the cellular context in which it functions. The research proposed here will identify and functionally characterize the factors that establish this context and those that act to implement specific ray cell fates. Among other characteristics, the genetic sophistication of C. elegans and the ability to observe development and marker gene expression in live animals make the nematode an ideal model for addressing these issues. This proposal outlines three related aims to test our hypothesis by characterizing the regulatory network that coordinates ray development. (1) We will test the novel model that regulated asymmetric lin-32 expression patterns ray cell fates in one branch of the ray sublineage, and explore the role of Wnt/MAPK signaling in this process. (2) We will examine the role of the LIM-HD gene lim-7 in the specification of RnB neuron subtype and determine its relationship to lin-32. (3) We will carry out a novel forward genetic screen and molecularly clone two new genes that act to control neural patterning in the ray sublineage. These studies will define the genetic mechanisms that determine the specificity of proneural gene function and the establishment of neural subtypes in a simple and tractable model. Understanding these mechanisms is essential both for a full appreciation of human neurodevelopmental disease and for the design of rational therapies. Lay summary: Using a small soil roundworm, we will explore the genetic mechanisms that generate cellular complexity in the nervous system. This has special relevance for human diseases in which these processes are disrupted.