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转录因子中具有关键的保守作用。 神经前体细胞的群体和控制其后代的分化。了解 这些因素的多重、性质上不同的功能是发育神经科学的中心目标。的 这项研究的长期目标是在分子遗传学水平上确定 C.秀丽线虫原神经基因lin-32控制从单个神经细胞产生三种不同的神经细胞类型。 神经前体细胞这三种细胞类型（两种称为RnA和RnB的神经元和一种神经胶质样结构细胞， Rnst）共同构成了栉孔扇贝的一种典型感觉器官--射线感器。elegans雄性尾巴。我们假设 射线前体细胞的后代是由转录级联组合指定的， 取决于LIN-32和它发挥作用的细胞环境。本文提出的研究将 确定和功能特性的因素，建立这种情况下，那些行动，以实现 特殊的射线细胞命运。在其他特征中，C.优雅和能力， 在活体动物中观察线虫的发育和标记基因的表达，使线虫成为研究的理想模型。 解决这些问题。该提案概述了三个相关的目标，以测试我们的假设， 协调射线发育的调节网络。(1)我们将测试新的模型， lin-32不对称表达模式的射线细胞命运在射线亚系的一个分支，并探讨其作用 Wnt/MAPK信号通路在这个过程中的作用。(2)我们将研究LIM-HD基因lim-7在肿瘤发生中的作用。 说明RnB神经元亚型并确定其与lin-32关系。(3)我们将推出一部小说 向前遗传筛选和分子克隆两个新的基因，以控制神经模式的射线 亚谱系这些研究将确定决定前神经特异性的遗传机制。 基因功能和神经亚型的建立在一个简单和易于处理的模型。理解 这些机制对于充分认识人类神经发育疾病和 合理治疗的设计。 使用一个小的土壤蛔虫，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殊意义，其中这些过程 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.