The Significance of Regulating Shh Signaling in Cortical Progenitor Specification

描述（由申请人提供）：哺乳动物的新皮层由分子和功能上不同的投射神经元组成，促进复杂的认知、感觉和运动能力。在胚胎发育过程中，皮层投射神经元由异质祖细胞群产生。特定神经元亚型的产生需要在祖细胞增殖、特化和分化过程中分子和细胞事件的精细协调。这些过程中的任何一个出现异常都可能导致神经系统疾病。因此，全面研究控制这些发育过程的机制事件对于了解这些疾病的分子和细胞基础至关重要。本研究将研究Sonic Hedgehog （Shh）信号通路的调控如何影响皮质祖细胞分化为特定的投射神经元亚型。特别是，融合抑制因子（Sufu）的作用，Shh信号的关键负调节因子，将被检查。初步研究表明，在神经发生早期，皮质祖细胞有条件地缺失素可导致投射神经元亚型的异常。基于这些初步发现，本建议的主要假设是Sufu在神经发生早期对Shh信号的严格调控对于皮质祖细胞的规范及其将产生的特定投射神经元亚型至关重要。这一假设将在以下目标中进行检验，使用组织学、共聚焦显微镜和信号/功能蛋白分析技术：特定目标1：确定Shh抑制的缺失如何影响胚胎神经发生过程中皮质祖细胞的规范和分化。特异性目的2：确定Shh信号的抑制是否调节皮层祖细胞的早期生成，这些祖细胞将产生上层神经元。申请人，Odessa Yabut博士，博士后学者，主要研究方向为哺乳动物前脑发育机制。Yabut博士将利用NRSA提供的机会，在胚胎发育过程中获得皮层祖细胞规范的广泛知识。Yabut博士将在Samuel Pleasure博士的指导下进行这些研究，Samuel Pleasure博士是神经发育领域的知名科学家。在Pleasure博士的指导下，Yabut博士将能够提高她在皮质祖细胞规范和分化的调节机制方面的知识，磨练她的批判性思维技能，并帮助她过渡到成为一名独立的学术科学家，因为她将这个项目发展成为未来在她自己的实验室进行研究的基础。

DESCRIPTION (provided by applicant): The mammalian neocortex is composed of molecularly and functionally distinct projection neurons that facilitate sophisticated cognitive, sensory, and motor abilities. Cortical projection neurons arise from a heterogeneous population of progenitor cells during embryonic development. The generation of specific neuronal subtypes requires the fine orchestration of molecular and cellular events during progenitor proliferation, specification, and differentiation. Anomalies in any one of these processes could lead to neurological disorders. Therefore, a comprehensive study of the mechanistic events that govern these developmental processes is crucial in order to understand the molecular and cellular basis of these diseases. This proposal will investigate how the regulation of Sonic Hedgehog (Shh) signaling pathway affects the specification of cortical progenitor cells into specific projection neuron subtypes. In particular, the role of Suppressor of Fused (Sufu), a critical negative regulator of Shh signaling, will be examined. Preliminary studies show that conditional deletion of Sufu from cortical progenitors early in neurogenesis lead to the abnormal specification of projection neuron subtypes. Based on these initial findings, the primary hypothesis of this proposal is that the tight regulation of Shh signaling by Sufu early in neurogenesis is critical for the specification of cortical progenitors and the specific projection neurons subtypes it will generate. This hypothesis will be tested in the following aims using techniques in histology, confocal microscopy, and signaling/functional protein analyses: Specific Aim 1: Determine how loss of Shh inhibition affects the specification and differentiation of cortical progenitors during embryonic neurogenesis. Specific Aim 2: Determine if inhibition of Shh signaling regulates early generation of cortical progenitors destined to generate upper layer neurons. The applicant, Odessa Yabut, Ph.D., is a postdoctoral scholar who is primarily interested in the mechanisms governing mammalian forebrain development. Dr. Yabut will take advantage of the opportunities offered by the NRSA to gain extensive knowledge in cortical progenitor specification during embryonic development. Dr. Yabut will conduct these studies under the guidance of Samuel Pleasure, M.D., Ph.D., who is an established scientist in the neural development field. With Dr. Pleasure's mentorship, Dr. Yabut will be able to enhance her knowledge on the regulatory mechanisms governing cortical progenitor specification and differentiation, hone her critical thinking skills, and help in her transition towards becoming an independent academic scientist as she develops this project into one that could be the basis of the research to be conducted in her own lab in the future.