The Significance of Regulating Shh Signaling in Cortical Progenitor Specification

描述（由申请人提供）：哺乳动物新皮层由分子和功能不同的投射神经元组成，这些投射神经元促进复杂的认知、感觉和运动能力。皮质投射神经元起源于胚胎发育过程中的异质祖细胞群体。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编排。这些过程中的任何一个异常都可能导致神经系统疾病。因此，为了了解这些疾病的分子和细胞基础，对控制这些发育过程的机制事件进行全面研究至关重要。 本研究将探讨Sonic Hedgehog（Shh）信号通路的调控如何影响皮质祖细胞分化为特定投射神经元亚型。特别是，融合的抑制（Sufu），一个关键的负调节Shh信号的作用，将被检查。初步研究表明，在神经发生早期，从皮层祖细胞中有条件地删除Sufu导致投射神经元亚型的异常特化。基于这些初步的发现，这个建议的主要假设是，Shh信号的严格调节，在神经发生的早期由Sufu是皮质祖细胞的规格和特定的投射神经元亚型，它将产生的关键。这一假设将在以下目标中使用组织学，共聚焦显微镜和信号/功能蛋白分析技术进行测试：具体目标1：确定Shh抑制的丧失如何影响胚胎神经发生过程中皮质祖细胞的特化和分化。具体目标2：确定Shh信号传导的抑制是否调节注定产生上层神经元的皮质祖细胞的早期产生。申请人敖德萨雅布特博士，是一位博士后学者，主要对哺乳动物前脑发育的机制感兴趣。Yabut博士将利用NRSA提供的机会，在胚胎发育过程中获得皮质祖细胞规范的广泛知识。Yabut博士将在Samuel Pleasure，M.D.的指导下进行这些研究，博士，他是神经发育领域的知名科学家Yabut将能够提高她对皮质祖细胞规范和分化的调控机制的知识，磨练她的批判性思维能力，并帮助她成为一名独立的学术科学家，因为她将这个项目发展成为一个可以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.