The molecular basis of neuronal circuit formation

神经系统的发育大致可分为两个阶段。首先，指定了各种类型的神经细胞。其次，神经细胞迁移到适当的位置，发出细小的突起(轴突和树突)，并通过形成突触连接与靶细胞连接。我的研究小组正在研究第二阶段的分子机制，特别是轴突寻径导致神经元回路的形成。我的研究计划的总体目标是剖析和理解神经元回路形成的基本分子机制。为此，拟议的研究重点是识别参与轴突寻路的缺失分子成员。在目标1中，我们将描述我们最近发现的几个新的轴突引导受体，并继续筛选其他受体的候选基因列表。其中一个受体是一种可能的神经肽受体。这是神经肽在轴突导航过程中作为潜在的轴突导航线索作用的(间接)证据。因此，我们计划更详细地描述神经肽在轴突寻路中的作用。在目标2和目标3中，我们将解决尚未解决的问题，即轴突如何在轴突束中正确定位。这对于正确的突触形成和神经元回路形成是必不可少的。这个问题在过去无法有效解决，因为需要使用电子显微镜研究来检测单个轴突水平的定位缺陷。超分辨率显微镜的发展使我们现在可以开发和使用光学显微镜标记来识别负责轴突定位的分子。 综上所述，这些实验将确定建立神经元回路所需的大量新的假定轴突引导受体。由于从无脊椎动物到脊椎动物，所有已知的轴突引导系统在进化上都是保守的，我们的研究将为神经元回路的一般形成方式提供实质性的见解，并为研究脊椎动物模式生物的研究人员提供重要的见解，以了解脊椎动物大脑发育的分子基础。

The development of the nervous system can be subdivided broadly into two phases. First, the various types of nerve cells are specified. Second, nerve cells migrate to their proper locations, send out thin processes (axons and dendrites) and connect to target cells by forming synaptic connections. My research group is studying the molecular mechanism underlying the second phase, specifically axonal pathfinding leading to the formation of neuronal circuits. The overall goal of my research program is to dissect and understand the fundamental molecular mechanisms underlying neuronal circuit formation. To this end the proposed research focuses on the identification of the missing molecular players involved in axonal pathfinding. In objective 1 we will characterize several novel axon guidance receptors that we recently identified and continue to screen a list of candidate genes for additional receptors. One of the receptors is a putative neuropeptide receptor. This is (indirect) evidence that neuropeptides act during axonal navigation as potential cues for navigating axons. Thus we plan to characterize the role of neuropeptides in axon pathfinding in more detail. In objectives 2 and 3 we will address the unresolved question of how axons are positioned properly within an axon bundle. This is essential for correct synapse formation and neuronal circuit formation. This question could not be addressed effectively in the past, because of the need to use electron microscopic studies to detect positioning defects at the single axon level. The development of super-resolution microscopes allows us now to develop and use light-microscopic markers to identify the molecules responsible for axon positioning. Taken together these experiments will identify a substantial number of novel putative axon guidance receptors required to establish neuronal circuits. Since all known axon guidance systems are evolutionarily conserved from invertebrates to vertebrates, our studies will provide substantial insights into the way neuronal circuits are formed in general and provide researchers working with vertebrate model organisms important insights into the molecular basis of vertebrate brain development.