Regulation of Cortical Circuit Development by Sonic Hedgehog Signaling

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伴侣的海洋中导航，以建立功能电路所需的适当突触连接。了解与特异性连接相关的细胞和分子机制对于我们解决诸如自闭症、精神分裂症和癫痫等无数神经系统疾病的能力至关重要，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发生改变。本研究的目的是了解在皮质发育过程中分泌分子Sonic Hedgehog如何传递突触偏好。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。首先作为一种形态因子调节神经系统的增殖和背腹侧模式，后来在发育中的脊髓和视网膜中作为轴突引导线索。人类SHH突变与广泛的临床症状相关，从严重的大脑畸形（前脑畸形）到轻度的学习障碍和语言习得延迟。这些基因研究表明，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Shh在皮层中的功能。先前我已经证明Shh在主要位于皮质层V和VI的皮层下投射神经元的特定群体中表达，而Sonic Hedgehog受体Boc在局部和巨大的投射神经元的互补群体中表达。我们进一步表明，Boc和Shh的表达对于II/III层到V层突触连接的发展是必需的。这些结果使我们假设发育中的皮层中Shh信号成分的神经细胞类型特异性表达是特定皮层回路发育所必需的。我们提出表征发育中的皮层中Shh信号成分Shh， Ptch1, Smo， Boc的细胞类型特异性和细胞定位。然后，我们将评估这些成分促进皮质回路发育的机制，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

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.