Molecular mechanisms of growth cone invasion

项目摘要 神经系统的发育需要适当的分化、迁移、形态发生和 神经元的成熟。单个神经元的形态分化和数万亿神经元的组装 组成人类神经系统的神经元连接是通过轴突的引导延伸和 树枝状结构。我们研究的长期目标是更好地了解细胞内的信号级联 以及负责发育中大脑中轴突生长和引导的效应器机制。为 这一点我们必须了解神经生长锥是如何检测、整合和反应可溶性的，以及细胞-和 底物相关的引导分子在他们的环境中。参与检测的基因突变 轴突引导信息向定向突起生长的转导对许多神经元的生长起作用。 发育障碍，包括自闭症、阅读障碍、心理障碍和认知缺陷。 因此，我们的工作旨在更好地理解正常神经发育的分子基础，可能 帮助告知导致神经网络组装异常的情况的治疗方法。 虽然广泛的研究已经研究了调节轴突引导的分子机制，但在两种情况下- 在体外或体内沿着轴突轨迹的维度底物，对控制轴突的信号知之甚少 在三维组织中进行引导。我们的初步数据和最近公布的数据表明， 有了平面丝状足基和片状伪足，生长锥体在体外和体内产生了正交的突起， 类似于足体或侵袭体。足体和拟足目，统称为 侵袭体是以肌动蛋白为基础的细胞突起，与细胞外基质(ECM)的降解和 组织侵入。我们假设生长锥侵入体的功能是通过主动检测配体 调节肌动蛋白聚合并参与配体和受体降解的受体相互作用 调节配体介导的导向。这项提议的三个目标将使用一系列分子增益 功能操作的功能和损失，以及超分辨率三维荧光 成像，以评估控制侵袭体形成的信号及其在控制神经网络中的作用 队形。

Project Summary The development of the nervous system requires the proper differentiation, migration, morphogenesis and maturation of neurons. The morphological differentiation of individual neurons and assembly of the trillions of neuronal connections that compose the human nervous system occurs through guided extension of axons and dendrites. The long-term objective of our research is to better understand the intracellular signaling cascades and effector mechanisms that are responsible for axon outgrowth and guidance in the developing brain. For this we must understand how nerve growth cones detect, integrate and respond to soluble, as well as cell- and substratum-associated guidance molecules in their environment. Mutations in genes involved in the detection and transduction of axon guidance information into directed neurite outgrowth are responsible for many neuro- developmental disorders, including autisms, dyslexias, psychological disorders and cognitive deficits. Therefore, our work aimed at better understanding the molecular basis of normal neural development, may help inform treatments for conditions leading to abnormal neural network assembly. While extensive studies have investigated the molecular mechanisms that regulate axon guidance over two- dimensional substrata in vitro or along axonal tracks in vivo, little is known about the signals that control axon guidance across three-dimensional tissues. Our preliminary and recently published data suggest that along with planar filopodia and lamellipodia, growth cones generate orthogonal protrusions in vitro and in vivo that resemble podosomes or invadopodia. Podosomes and invadopodia, collectively referred to as invadosomes, are actin-based cellular protrusions associated with extracellular matrix (ECM) degradation and tissue invasion. We hypothesize that growth cone invadosomes function to actively detect ligands through receptor interactions that regulate actin polymerization and participate in ligand and receptor degradation to modulate ligand-mediated guidance. The three aims of this proposal will use a series of molecular gain of function and loss of function manipulations, together with super resolution three-dimensional fluorescence imaging, to assess the signals that control invadosome formation and their roles in controlling neural network formation.