MET receptor tyrosine kinase and the development of forebrain circuits

人类遗传学研究已确定Met是自闭症谱系障碍的显著风险基因，是一种高度危险的疾病 遗传性精神障碍，神经连接个体发育中断。MET蛋白是一种受体酪氨酸 在大脑发育早期受到严格调控的一种激酶，在轴突快速生长和 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 通过研究时间限制信号如何调节关键大脑发育来阐明时间限制信号的性质 事件，包括突触发生、成熟、回路连接和精炼。调查的初步结果 Pi的实验室显示，干扰MET信号会导致小鼠皮质层间兴奋性改变 谷氨酸能突触的连通性、异常神经元形态和成熟以及受损 电路连通性表明有缺陷的突触修剪和电路精炼。使用可控制的 在实验室创造的转基因小鼠模型中，这个研究小组最近发现了MET的激活 参与Rho家族小GTP酶，cdc42和rac1，并导致肌动蛋白解聚的抑制 因子cofilin，对树突棘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信号促进了早期树突棘的形态发生，而 它的下调是脑内树突棘和谷氨酸能突触成熟所必需的 发展。在这个应用程序中，研究小组聚集了一个跨学科的团队，并采取了 神经解剖学、分子遗传学、活体双光子成像和膜片钳相结合的综合方法 电生理学结合激光扫描光刺激进行电路标测，以测试以下各项 假设：1)正常的谷氨酸能突触需要MET表达的发育下调 成熟；2)持续的MET信号损害发育中的突触修剪和精化皮质回路 连接性；以及3)MET信号的中断和由此导致的前脑发育轨迹的改变 鼠标行为。影响：预计成功完成这些拟议研究将确定 MET在神经发育和功能建立中的深层次、机械性和多面性作用 发育中的前脑的连通性。这些机制总体上可能是MET独有的，并且可以 以谷氨酸能突触发育的时间分布为靶点阐明自闭症的新干预措施 在特定的大脑回路中。

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.