The Significance of Regulating Shh Signaling in Cortical Progenitor Specification

描述(申请人提供)：哺乳动物的新大脑皮层由分子和功能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，皮质投射神经元来源于不同种类的前体细胞。特定神经元亚型的产生需要在祖细胞增殖、指定和分化过程中对分子和细胞事件进行精细的协调。这些过程中的任何一个过程中的异常都可能导致神经障碍。因此，对支配这些发育过程的机制事件的全面研究对于了解这些疾病的分子和细胞基础是至关重要的。这项建议将研究Sonic Hedgehog(Shh)信号通路的调节如何影响皮质前体细胞到特定投射神经元亚型的规范。特别是，融合抑制因子(Sufu)，Shh信号的关键负调控因子，其作用将被研究。初步研究表明，在神经发生早期，皮层祖细胞的Sufu条件缺失导致投射神经元亚型的异常指定。基于这些初步发现，这一建议的主要假设是，Sufu在神经发生早期对Shh信号的严格调控对于皮质前体细胞及其将产生的特定投射神经元亚型的指定至关重要。这一假说将利用组织学、共聚焦显微镜和信号/功能蛋白分析技术在以下目标进行验证：特定目标1：确定Shh抑制的丧失如何影响胚胎神经发生过程中皮质前体细胞的指定和分化。具体目标2：确定Shh信号的抑制是否调节了预定产生上层神经元的皮质前体细胞的早期生成。申请者Odessa Yabut博士是一名博士后学者，他主要对哺乳动物前脑发育的机制感兴趣。雅布特博士将利用NRSA提供的机会，在胚胎发育期间获得有关皮质祖细胞规格的广泛知识。雅布特博士将在塞缪尔·普莱斯的指导下进行这些研究，他是神经发育领域的知名科学家，医学博士和博士。在愉悦博士的指导下，雅布特博士将能够增强她对控制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一个可能成为未来在她自己的实验室进行的研究的基础。

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.