Regulation of Cortical Circuit Development by Sonic Hedgehog Signaling

描述(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导航，才能建立起功能回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疾病的能力至关重要，如自闭症、精神分裂症和癫痫，在这些疾病中，特定的神经元连接以阻止正常网络功能的方式改变。这项研究的目的是了解分泌分子Sonic Hedgehog如何在皮质发育过程中传递突触偏好。Sonic Hedgehog(SHH)是一种分泌分子，在神经系统发育过程中具有许多关键功能。最初是作为一种形态原调节神经系统的增殖和背腹模式，后来作为发育中的脊髓和视网膜的轴突指导信号。人类SHH的突变与一系列临床症状有关，从严重的大脑畸形(全前脑)到较轻的学习障碍和语言获取的延迟。这些遗传学研究表明Shh功能可能不仅对神经系统的模式形成至关重要，而且可能在人类皮质回路的形成中发挥作用，并强调了我们在回路发育过程中了解Shh功能的必要性。以前我已经证明Shh在主要位于皮质V层和VI层的皮质下投射神经元的特定群体中表达，而Sonic Hedgehog受体Boc在局部和巨大投射神经元的互补群体中表达。我们进一步证明Boc和Shh的表达是第二层/第三层到第五层突触连接发展所必需的。这些结果使我们假设，发育中的皮质中Shh信号成分的神经细胞类型特异性表达是特定皮质回路发育所必需的。我们建议表征Shh信号成分Shh、ptch1、Smo、Boc在发育皮质中的细胞类型特异性和细胞定位。然后，我们将评估这些成分对皮质回路发育的贡献机制，以及它们对非规范Shh信号的依赖。最后，我们将测试Shh及其同源受体的表达是否足以改变皮质神经元的突触偏好。在……里面 为了达到我在哈佛医学院神经生物学系获得终身教职的最终目标，我制定了职业发展计划，并成立了一个导师委员会，由系内终身教职员工组成。罗莎琳德·西格尔博士将担任我的主要导师，系主任迈克尔·格林伯格博士和终身教授韦德·雷格尔博士将担任共同导师。我选择了我的指导委员会的每一位成员，因为他们在实验室和部门层面都有丰富的指导记录。我之所以选择这个特殊的群体，也是因为他们的科学专长领域，以及 我将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事业成功的三个主要方面。1)以实验室管理和组织为重点的指导和指导。2)我独立研究项目的发展和壮大。3)导航机构职责和履行晋升和终身教职的要求，扩大我的科学网络和形象。

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.