GABAergic Neuron Differentiation in C.elegans

在生物体的一生中，突触的增加和消除是持续进行的，以确保适当的 神经回路的功能。越来越多的证据表明，复杂的相互作用涉及内在 以及突触细化中的外在因素，具有时间和神经元类型的特异性。利用C. 线虫继续通过单一的-基因途径扩展对分子和遗传途径的理解 突触解析。运动回路由几类兴奋性胆碱能马达组成。 神经元和两类GABA能运动神经元，是一个很容易发现的系统 突触形成和细化的潜在机制。每个神经元形成千篇一律的模式 突触的数量，提供准确的读数来检查突触是如何动态调节的。 此外，成熟的运动电路的开发涉及到对 在没有轴突的情况下，胚胎出生的GABA能神经元被称为“DD突触重塑” 形态变化。我们开发了第一个活体可视化方法来检查DD突触 改建。在我们最近的研究中，我们定义了微管动力学在促进 在DD重塑中，货物和运动在形成新突触中的相互作用。我们的发现强调了 微管不是被动的轨迹，而是在细胞信号中发挥积极作用的概念。在 此更新申请的具体目标1我们将利用我们在基因途径解剖方面的专业知识 通过体内微管组件成像来剖析一种新的激酶在DD突触中的作用 改建。同时，我们还研究了胆碱能神经元的调节机制。 突触，并发现了由IgSF跨膜介导的组织间相互作用的作用 结构域蛋白ZIG-10。我们的研究表明，ZIG-10通过SRC激酶调节吞噬途径 在邻近的非神经性组织中。在具体目标2中，我们将处理细胞活动和 使用创新技术对这一途径的生理影响。我们将进一步研究神经元是如何 活动调节这一途径。在目标3中，我们将研究一个保守的Maguk蛋白的作用，该蛋白 可能将ZIG-10通路与突触维持过程中磷脂的生物合成联系起来。基因突变 人类中的同源分子与各种神经疾病有关。在一起我们的 这些发现将为潜在的信令网络提供重要的见解，并促进我们的知识 对人类疾病的理解。

Throughout a lifetime of an organism synapse addition and elimination is on-going to ensure proper function of neuronal circuits. Growing evidence have revealed complex interactions involving intrinsic and extrinsic factors in synapse refinement with temporal and neuronal-type specificity. Studies using C. elegans have continued to expand the understanding of molecular and genetic pathways with single- synapse resolution. The locomotor circuit consists of several classes of excitatory cholinergic motor neurons and two classes of GABAergic motor neurons, and is a highly tractable system to discover mechanisms underlying synapse formation and refinement. Each neuron forms stereotyped pattern and number of synapses, providing an accurate readout to examine how synapses are dynamically regulated. Moreover, the development of the mature locomotor circuit involves a precisely timed remodeling of the embryonically born GABAergic neurons, known as “DD synapse remodeling”, in the absence of axonal morphological changes. We developed the first in vivo visualization approach to examine DD synapse remodeling. In our recent studies, we have defined critical roles of microtubule dynamics in promoting cargo and motor interaction in the formation of new synapses in DD remodeling. Our findings underscore the concept that microtubules are not passive tracks but play an active role in cellular signaling. In the specific Aim 1 of this renewal application we will leverage our expertise in genetic pathway dissection with in vivo imaging of microtubule components to dissect the roles of a novel kinase in DD synapse remodeling. In parallel, we have investigated the mechanisms regulating the cholinergic neuron synapses, and have uncovered roles of inter-tissue interaction mediated by a IgSF transmembrane domain protein ZIG-10. Our studies show that ZIG-10 regulates phagocytotic pathway via a SRC kinase in the adjacent non-neuronal tissues. In specific Aim 2, we will tackle the cellular action and the physiological impact of this pathway using innovative technologies. We will further examine how neuronal activity regulates this pathway. In Aim 3, we will investigate the role of a conserved MAGUK protein that may link the ZIG-10 pathway to phospholipid biosynthesis in synapse maintenance. Genetic mutations of homologous molecules in human have been linked to various neurological diseases. Together our findings will provide important insights to the underlying signaling network and advance our knowledge in the understanding of human diseases.