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Regulation of synaptic specificity by two Ig-domain containing families

两个含有 Ig 结构域的家族对突触特异性的调节

基本信息

批准号：
9330947
负责人：
Matthew Yasuo Pecot
金额：
$ 21.72万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9330947
关键词：
Address Affect Afferent Neurons Alpha Cell Architecture Axon Behavior Binding Biomedical Research Brain Cells Cellular biology Communication Complex Defect Dendrites Department chair Development Development Plans Disease Drosophila genus Electron Microscopy Environment Epilepsy Eye Faculty Family Future Gene Targeting Genes Genetic Goals Growth Health Human Immunoglobulin Domain Immunoglobulins In Vitro Individual Intellectual functioning disability Invertebrates Investigation Knowledge Learning Light Mentors Methods Molecular Motion Multiple Partners Muscle Nervous System Physiology Nervous system structure Neurobiology Neurons Neurosciences Research Optic Lobe Pattern Photoreceptors Process Proteins Regulation Research Research Personnel Role Schizophrenia Sensory Specificity Stereotyping Synapses Synaptic Potentials Testing Therapeutic Vertebrates Visual system structure autism spectrum disorder axon guidance base career career development cell type collaborative environment design experience experimental study fly gain of function in vivo light microscopy medical schools member mid-career faculty nervous system disorder neural circuit neuron development novel overexpression parallel processing professor programs public health relevance relating to nervous system response skills synaptogenesis tool visual information

项目摘要

DESCRIPTION (provided by applicant): The nervous system comprises tremendous cellular complexity yet its function relies on neurons forming precise patterns of synaptic connections. How individual neurons find and form synapses with the correct partners amidst so many inappropriate ones remains poorly understood. Recent evidence indicates that defects in neural connectivity are an underlying cause of neurological disorders. Thus, identifying molecular mechanisms underlying synaptic connectivity is of major importance to biomedical research and human health. Within the visual systems of vertebrates and invertebrates neurons target axons or dendrites to discrete layers wherein they form synaptic connections, thereby providing a structural basis for the parallel processing of different visual information. In the fly optic lobe synaptic layers contain synapses from many neurons, yet specific neurons within a layer synapse with only a subset of these. How synaptic specificity within layers is achieved is unknown. We have discovered that two families of immunoglobulin (Ig) domain-containing proteins known to engage in heterothallic inter-family interactions are expressed complementarily in a cell-type and layer-specific manner within the fly optic lobe. Different afferent cell types express unique combinations of Dprs (21 genes), and target neurons express Dpr interacting proteins or DIPs (11 members). We hypothesize that different heterothallic Dpr-DIP interactions provide a common mechanism by which afferent neurons establish unique patterns of synaptic connections. To test this hypothesis we will investigate Dpr and DIP function in regulating synaptic specificity within a single afferent cell type, L3 lamina monopolar neurons which synapse with multiple partners within their target layer. We will identify cognate Dpr-DIP pairs expressed by L3 neurons and their synaptic partners and investigate their role in synapse formation. We will also perform gain of function experiments to assess if these Dpr-DIP interactions are sufficient to promote synaptic connectivity. The goal of this research is to identify a molecular strategy underlying synaptic specificity. These studies are designed to address a fundamental gap in our knowledge of the molecular mechanisms underlying neural connectivity and establish a platform for the long term investigation of this issue. We anticipate this research will shed light on strategies for rewiring neural circuits in individuals affected by neurological disease and for creating neural circuits with novel functions. To achieve my short term career goal of establishing an independent research program and earning promotion to Associate Professor in the Department of Neurobiology at Harvard Medical School, and my long term career goal of achieving tenure within the Department, I have assembled a team of mentors consisting of tenured faculty at Harvard Medical School who have helped me establish a career development plan. David Ginty, a Professor in the Department of Neurobiology will serve as my primary mentor, and Michael Greenberg, Professor and Chair of the Department of Neurobiology, and David Van Vactor, Professor in the Department of Cell Biology will be co-mentors. Each member will contribute to my growth as an independent investigator in complementary ways based on their scientific expertise and experience. My career development activities will be focused on: (1) Improvement of mentoring, management and lab organization skills (2) Development of my research program (3) Learning how to best fulfill my institutional responsibilities. Based on my strong career development plan, the expertise of my mentor team and the supportive environment within the Department of Neurobiology and Harvard Medical School I believe I have an excellent opportunity to achieve my career goals.

描述（由申请人提供）：神经系统包括巨大的细胞复杂性，但其功能依赖于神经元形成突触连接的精确模式。单个神经元是如何在如此多的不合适的神经元中找到并与正确的神经元形成突触的，人们对此知之甚少。最近的证据表明，神经连接的缺陷是神经系统疾病的根本原因。因此，识别突触连接的分子机制对生物医学研究和人类健康具有重要意义。在脊椎动物和无脊椎动物的视觉系统中，神经元将轴突或树突靶向到离散层，在离散层中它们形成突触连接，从而为不同视觉信息的并行处理提供结构基础。在果蝇的视叶突触层包含许多神经元的突触，但特定的神经元在一个层突触只有这些子集。层内的突触特异性是如何实现的尚不清楚。我们已经发现，两个家庭的免疫球蛋白（IG）结构域的蛋白质已知从事异宗配合物家族间的相互作用互补表达的细胞类型和层的特定方式内的苍蝇视叶。不同的传入细胞类型表达Dpr的独特组合（21个基因），靶神经元表达Dpr相互作用蛋白或DIP（11个成员）。我们假设，不同的异宗配合Dpr-DIP相互作用提供了一个共同的机制，传入神经元建立独特的模式的突触连接。为了验证这一假设，我们将研究Dpr和DIP在调节单个传入细胞类型（L3板单极）内突触特异性中的功能与目标层内的多个伙伴突触的神经元。我们将确定同源Dpr-DIP对L3神经元和它们的突触伙伴表达，并研究它们在突触形成中的作用。我们还将进行功能增益实验，以评估这些Dpr-DIP相互作用是否足以促进突触连接。本研究的目的是确定突触特异性的分子策略。这些研究旨在解决我们对神经连接的分子机制的认识中的一个根本空白，并为长期研究这个问题建立一个平台。我们预计这项研究将阐明在受影响的个体中重新连接神经回路的策略。神经疾病和创造具有新功能的神经回路。为了实现我的短期职业目标，即建立一个独立的研究项目，并晋升为哈佛医学院神经生物学系副教授，以及我的长期职业目标，即在该系获得终身教职，我组建了一个由哈佛医学院终身教职人员组成的导师团队，他们帮助我制定了职业发展计划。大卫金蒂，在神经生物学系教授将担任我的主要导师，和迈克尔格林伯格，教授和神经生物学系主任，和大卫货车Vactor，在细胞生物学系教授将共同导师。每个成员都将根据他们的科学专业知识和经验，以互补的方式为我作为独立研究者的成长做出贡献。我的职业发展活动将集中在：（1）指导，管理和实验室组织技能的提高（2）我的研究计划的发展（3）学习如何最好地履行我的机构职责。基于我强大的职业发展计划，我的导师团队的专业知识以及神经生物学系和哈佛医学院的支持环境，我相信我有一个很好的机会来实现我的职业目标。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Control of Synaptic Specificity by Establishing a Relative Preference for Synaptic Partners.

通过建立突触伙伴的相对偏好来控制突触特异性。

DOI：
10.1016/j.neuron.2020.04.007
发表时间：
2020
期刊：
Neuron
影响因子：
16.2
作者：
Xu,Chundi;Theisen,Emma;Maloney,Ryan;Peng,Jing;Santiago,Ivan;Yapp,Clarence;Werkhoven,Zachary;Rumbaut,Elijah;Shum,Bryan;Tarnogorska,Dorota;Borycz,Jolanta;Tan,Liming;Courgeon,Maximilien;Griffin,Tessa;Levin,Raina;Meinertzhagen,I
通讯作者：
Meinertzhagen,I

Drosophila Fezf coordinates laminar-specific connectivity through cell-intrinsic and cell-extrinsic mechanisms.

DOI：
10.7554/elife.33962
发表时间：
2018-03-07
期刊：
eLife
影响因子：
7.7
作者：
Peng J;Santiago IJ;Ahn C;Gur B;Tsui CK;Su Z;Xu C;Karakhanyan A;Silies M;Pecot MY
通讯作者：
Pecot MY

Strategies for assembling columns and layers in the Drosophila visual system.