Regulation of Cortical Circuit Development by Sonic Hedgehog Signaling

声波刺猬信号对皮层回路发育的调节

• 批准号: 8926481
• 负责人: COREY C HARWELL
• 金额: $ 22.25万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8926481
• 关键词: Address; Animals; Area; Autistic Disorder; Axon; Behavior; Cellular Assay; Cerebral cortex; Clinical; Cognition Disorders; Complex; Cues; Dependence; Development; Development Plans; Epilepsy; Erinaceidae; Faculty; Genetic; Genetic study; Goals; Growth; Growth and Development function; Health; Histology; Holoprosencephaly; Human; Individual; Intellectual functioning disability; Knock-out; Laboratories; Lead; Learning Disabilities; Mentors; Mentorship; Molecular; Mutation; Nervous system structure; Neurobiology; Neurons; Pattern; Performance; Phenotype; Physiological; Population; Process; Records; Regulation; Reporter; Research; Retina; Role; Schizophrenia; Sea; Signal Transduction; Specificity; Speech; Spinal Cord; Symptoms; Synapses; Technical Expertise; Testing; Work; axon guidance; brain malformation; career; career development; cell type; combinatorial; effective therapy; medical schools; member; morphogens; nervous system development; nervous system disorder; neuron development; preference; prevent; professor; programs; receptor; smoothened signaling pathway; sonic hedgehog receptor; success; synaptogenesis

DESCRIPTION (provided by applicant): During development neurons in the cortex must navigate through a sea of potential partners in order make the proper synaptic connections required for functional circuitry. Understanding the cellular and molecular mechanisms involved in the specificity of connections is crucial to our ability address a myriad of neurological disorders such as autism, schizophrenia, and epilepsy, in which specific neuronal connections are altered in ways that prevent normal network function. The objective of this study is to understand how the secreted molecule Sonic Hedgehog functions to convey synaptic preferences during cortical development. Sonic Hedgehog (SHH) is a secreted molecule that has numerous critical functions during nervous system development. First as a morphogen regulating proliferation and dorsoventral patterning of the nervous system, and later as an axon guidance cue in the developing spinal cord and retina. Mutations of SHH in humans are associated with a broad range of clinical symptoms, ranging from severe malformation of the brain (holoprosencephaly) to milder learning disabilities and delays in speech acquisition. These genetic studies suggest that Shh function may not only be critical for the patterning of the nervous system, but also may have roles in human cortical circuit formation, and highlight our need to understand Shh function in the cortex during circuit development. Previously I've shown that Shh is expressed in specific populations of subcortical projection neurons located primarily in cortical layers V and VI, while the Sonic Hedgehog receptor Boc is expressed in a complementary population of local and colossal projection neurons. We further showed that Boc and Shh expression is required for the development of layer II/III to layer V synaptic connections. These results have lead us to hypothesize that neural cell type specific expression of Shh signaling components in the developing cortex is required for the development of specific cortical circuits. We propose to characterize the cell type specificity and cellular localization o Shh signaling components Shh, Ptch1, Smo, Boc, in the developing cortex. We will then assess the mechanism by which these components contribute to the development of cortical circuitry, and their dependence on noncanonical Shh signaling. Finally, we will test if expression of Shh and its cognate receptors are sufficient to alter the synaptic preferences of cortical neurons. In order to reach my ultimate goal of achieving tenure in the Department of Neurobiology at Harvard Medical School, I have developed a career development plan and formed a committee of mentors, consisting of tenured faculty in the department. Dr. Rosalind Segal will serve as my primary mentor, with the department chair, Dr. Michael Greenberg and tenured professor Dr. Wade Regehr serving as co-mentors. I have chosen each member of my mentoring committee because of their extensive track records of mentorship both at the laboratory and departmental level. I have also chosen this particular group because of their areas of scientific expertise, and the technical and scientific advice that I stand to gain from our mentoring relationship. My career development activities will be focused on three major aspects to my career success. 1) Mentorship and guidance focused on laboratory management and organization. 2) The development and growth of my independent research program. 3) Navigating institutional responsibilities and fulfilling requirements for promotion and tenure and expanding my scientific network and profile.

描述（由申请人提供）：在发育过程中，皮层中的神经元必须在潜在伙伴的海洋中航行，以便形成功能电路所需的适当突触连接。了解连接特异性所涉及的细胞和分子机制对于我们解决无数神经系统疾病的能力至关重要，例如自闭症，精神分裂症和癫痫，其中特定的神经元连接以阻止正常网络功能的方式改变。本研究的目的是了解分泌分子Sonic Hedgehog在皮质发育过程中如何传递突触偏好。Sonic Hedgehog（SHH）是一种分泌型分子，在神经系统发育过程中具有许多关键功能。首先作为一种形态原调节神经系统的增殖和背腹图案，后来作为发育中的脊髓和视网膜中的轴突引导线索。人类SHH的突变与广泛的临床症状有关，从严重的大脑畸形（前脑无裂畸形）到轻度的学习障碍和语言习得延迟。这些遗传学研究表明，Shh功能可能不仅对神经系统的模式至关重要，而且可能在人类皮层回路形成中发挥作用，并强调我们需要了解回路发育过程中皮层中的Shh功能。以前我已经表明，Shh表达在特定群体的皮质下投射神经元主要位于皮质层V和VI，而声刺猬受体Boc表达在一个互补的人口的本地和巨大的投射神经元。我们进一步表明，Boc和Shh的表达是所需的第II/III层到第V层突触连接的发展。这些结果使我们假设，神经细胞类型的特定表达的Shh信号成分在发育中的皮层是需要特定的皮层电路的发展。我们建议表征细胞类型特异性和细胞定位的Shh信号成分Shh，Ptch 1，Smo，Boc，在发育中的皮层。然后，我们将评估的机制，这些组件有助于发展的皮层电路，和他们的依赖非经典的Shh信号。最后，我们将测试Shh及其同源受体的表达是否足以改变皮层神经元的突触偏好。 在 为了实现我在哈佛医学院神经生物学系获得终身教职的最终目标，我制定了一个职业发展计划，并成立了一个导师委员会，由该系的终身教职人员组成。Rosalind Segal博士将担任我的主要导师，系主任Michael Greenberg博士和终身教授Wade Regehr博士将担任共同导师。我之所以选择我的指导委员会的每一位成员，是因为他们在实验室和部门层面都有广泛的指导记录。我之所以选择这一特殊群体，也是因为他们的科学专长领域， 我从我们的指导关系中获得的技术和科学建议。我的职业生涯 发展活动将集中在我职业成功的三个主要方面。1)导师和指导侧重于实验室管理和组织。2)我的独立研究项目的发展和成长。3)导航机构的责任和履行晋升和任期的要求，扩大我的科学网络和个人资料。