MET receptor tyrosine kinase and the development of forebrain circuits

MET 受体酪氨酸激酶与前脑回路的发育

基本信息

批准号：
9913595
负责人：
Shenfeng Qiu
金额：
$ 38.38万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9913595
关键词：
Address Affect Animals Behavior Behavioral Biochemical Brain Chronic Data Defect Dendritic Spines Development Disease Down-Regulation Electrophysiology (science)Etiology Event Excitatory Synapse Family Forebrain Development Functional disorder Genetic Genetic study Glutamate Receptor Glutamates Goals Growth Heritability Human Human Genetics Impairment Intervention Knowledge Laboratories Lasers Learning Location Long-Term Depression Long-Term Potentiation MET gene Maps Mediating Memory Mental disorders Metaplasia Methods Molecular Molecular Analysis Molecular Genetics Monomeric GTP-Binding Proteins Morphogenesis Morphology Mus Nature Neuroanatomy Neurodevelopmental Disorder Neurons Outcome Pathogenesis Pathologic Physiological Prefrontal Cortex Process Production Prosencephalon Proteins Public Health Receptor Protein-Tyrosine Kinases Research Risk Factors Rodent Model Role Scanning Shapes Signal Transduction Structure Synapses Testing Time TimeLine Transgenic Mice actin depolymerizing factor autism spectrum disorder behavior test cofilin cognitive function genetic risk factor in vivo in vivo two-photon imaging insight learned behavior morris water maze mouse model neural circuit neurite growth neurodevelopment neuromechanism neuropsychiatric disorder novel patch clamp protein profiling relating to nervous system rho risk variant social synaptogenesis

项目摘要

Human genetic studies have established MET as a prominent risk gene for autism spectrum disorder, a highly heritable psychiatric disorder with disrupted ontogeny of neural connectivity. MET protein is a receptor tyrosine kinase that is tightly regulated during early brain development, peaks at a period of rapid neurite growth and synaptogenesis, and is precipitously down-regulated prior to neuronal maturation. The goal of this project is to elucidate the nature of the time-delimited signaling by investigating how it regulates key brain development events, including synaptogenesis, maturation, circuit connectivity and refinement. Preliminary results from the PI's laboratory reveal that disruption of MET signaling in mice results in altered cortical interlaminar excitatory connectivity, aberrant neuronal morphology and maturation of glutamatergic synapses, as well as impaired circuit connectivity indicative of defective synapse pruning and circuit refinement. Using a controllable transgenic mouse model created in the lab of the PI, this research team recently found that MET activation engages the Rho family small GTPases, Cdc42 and Rac1, and leads to inhibition of the actin depolymerizing factor cofilin, processes that are critical for dendritic spine morphogenesis and excitatory synapse development. This has led to the central hypothesis that MET signaling promotes early dendritic spine morphogenesis, while its down-regulation is required for dendritic spine and glutamatergic synapse maturation later in brain development. In this application, the research group brings together an interdisciplinary team and takes an integrated approach combining neuroanatomy, molecular genetics, in vivo two photon imaging, and patch clamp electrophysiology combined with laser scanning photostimulation for circuit mapping to test the following hypotheses: 1) developmental down-regulation of MET expression is required for normal glutamatergic synapse maturation ; 2) persistent MET signaling impairs developmental synapse pruning and refinement cortical circuit connectivity; and 3) disrupted MET signaling and the resulting change in forebrain developmental trajectory alter mouse behavior. Impact: It is anticipated that successful completion of these proposed studies will define an in-depth, mechanistic, and multifaceted role of MET in neural development and establishment of functional connectivity in the developing forebrain. These mechanisms collectively may be unique to MET, and may illuminate novel interventions in autism by targeting the temporal profiles of glutamatergic synapse development in specific brain circuits.

人类遗传研究已经建立为自闭症谱系障碍的显着风险基因，这是一种高度可遗传的精神障碍，神经连通性的个体发育破坏。 MET蛋白是一种受体酪氨酸激酶在早期大脑发育过程中受到严格调节，在快速神经突生长和突触发生，并在神经元成熟之前急剧下调。这个项目的目标是通过研究如何调节关键大脑发育，阐明了时间推迟信号的性质事件，包括突触发生，成熟，电路连通性和改进。初步结果 PI的实验室表明，小鼠MET信号的破坏会导致皮质间兴奋性改变连通性，异常神经元形态和谷氨酸能突触的成熟以及受损电路连通性指示突触修剪和电路细化的缺陷。使用可控的在PI实验室创建的转基因小鼠模型，该研究团队最近发现MET激活参与Rho家族小GTPases，Cdc42和rac1，并导致抑制肌动蛋白去聚合因子Cofilin，对于树突状脊柱形态发生和兴奋性突触发育至关重要的过程。这导致了一个中心假设，即MET信号传导促进了早期的树突状脊柱形态发生，而它的下调是在大脑后来在大脑中成熟的树突状脊柱和谷氨酸能突触成熟的必需发展。在此应用程序中，研究小组汇集了一个跨学科团队，并采用了结合神经解剖学，分子遗传学，体内两个光子成像和斑块夹的综合方法电生理学与激光扫描光刺激进行电路映射以测试以下假设：1）正常谷氨酸能突触需要MET表达的发展下调成熟； 2）持续的MET信号传导会损害发育突触修剪和细化皮质回路连通性； 3）MET信号传导中断以及前脑发育轨迹的变化变化鼠标行为。影响：预计这些拟议研究的成功完成将定义 MET在神经发展和功能的建立中的深入，机械和多方面的作用发展前脑中的连通性。这些机制共同可能是MET独有的，并且可能通过靶向谷氨酸能突触发育的时间特征来照亮自闭症的新型干预措施在特定的脑电路中。