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（由适用提供）：神经系统包括巨大的细胞复杂性，但其功能依赖于形成突触连接精确模式的神经元。单个神经元如何与正确的伴侣在许多不适当的神经伴侣中发现并形成突触。最近的证据表明，神经元连通性缺陷是神经系统疾病的根本原因。这是对生物医学研究和人类健康至关重要的确定分子机制至关重要的。在脊椎动物和无脊椎动物的视觉系统中，神经元的神经元将轴突或树突靶向离散的层，它们在其中形成突触连接，从而为平行处理不同的视觉信息提供了结构性基础。在苍蝇叶片中，合成层包含来自许多神经元的突触，但在层突触中的特定神经元仅具有其中的一部分。如何实现层中的突触特异性是未知的。我们已经发现，已知参与异性植物间相互作用的含两个免疫球蛋白（IG）域的蛋白质在蝇叶中以细胞型和层特异性方式补充。不同的传入细胞类型表达了DPRS（21个基因）的独特组合，而靶神经元表达DPR相互作用的蛋白质或DIPS（11个成员）。我们假设不同的异质DPR-DPR相互作用提供了一种共同的机制，通过该机制传统神经元建立了突触连接的独特模式。为了检验该假设与目标层中多个伴侣突触的神经元。我们将确定L3神经元及其突触伙伴表达的DPR-DIP对，并研究它们在突触形成中的作用。我们还将执行功能实验的增益，以评估这些DPR-DIP相互作用是否足以促进突触连通性。这项研究的目的是确定突触特异性基本的分子策略。这些研究旨在解决我们了解神经连接性的分子机制的基本差距，并为该问题的长期投资建立平台。我们预计这项研究将揭示重新策略的策略神经疾病并创建具有新功能的神经环路。为了实现我的短期职业目标，即建立一个独立的研究计划并促进哈佛医学院神经生物学系副教授，以及我在该系中实现任期的长期职业目标，我召集了一个由哈佛医学院终身教师组成的导师团队，他们帮助我建立了职业发展计划。神经生物学系教授David Ginty将担任我的主要导师，而神经生物学系教授兼主席Michael Greenberg，细胞生物学系教授David van Vactor将担任合伙人。每个成员将根据他们的科学专业知识和经验，以完整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）改善心理，管理和实验室组织技能（2）我的研究计划的发展（3）学习如何最好地满足我的机构责任。根据我强大的职业发展计划，我的心理团队的专家以及神经生物学系和哈佛医学院内的支持环境，我相信我有一个极好的机会来实现自己的职业目标。

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

Purification of Low-abundant Cells in the Drosophila Visual System.

果蝇视觉系统中低丰度细胞的纯化。