Regulation of Sensory-Motor Connectivity by Semaphorin-Plexin Signaling

描述（由申请人提供）：神经元以精确的特异性建立突触连接，以组装神经回路。尽管控制初始轴突轨迹的分子相对较好地被理解，但在目标区域内如何形成精确的突触连接在很大程度上尚不清楚。该提案的目的是了解发育中的小鼠脊髓中突触形成和突触特异性的分子基础。脊髓中的脊髓反射回路是研究突触形成和突触特异性的优秀模型系统，因为它相对简单并且可以获得基于先前的解剖学和电生理学研究的丰富知识。腹侧灰质中的细胞体被分组为“运动神经元池”，它将轴突投射到特定的肌肉。在小鼠脊髓的四肢水平上大约有五十个这样的运动神经元池。 “本体感觉神经元”用本体感觉纤维支配这些肌肉，其细胞体位于背根神经节（DRG）中，并将轴突投射到脊髓中，脊髓终止并与适当的运动神经元池形成突触。我们的初步数据强烈表明信号配体的信号蛋白（sema）家族及其受体丛蛋白控制突触形成和感觉运动连接的突触特异性。首先，在所有 sema 和 plexin 中，只有 plexinA1、plexinD1 和 sema6B 的表达在本体感觉感觉神经元中高度富集。其次，当突触发生时，运动和本体感觉神经元表达 sema6D 及其受体 plexinA1。第三，plexinD1 由本体感觉感觉神经元亚群表达，而其配体 sema3E 由运动神经元亚群表达。我们假设 sema-plexin 组合控制发育中脊髓的突触形成和突触特异性。第一个目标是检查 sema6D-plexinA1 信号传导是否调节感觉运动连接的突触形成。第二个和第三个目标将检查 sema3E-plexinD1 和 plexinA4-sema6B 信号传导是否控制感觉运动连接的突触特异性。我们将通过结合解剖学、电生理学、行为学和体外分析以及小鼠遗传学来解决这些问题。

DESCRIPTION (provided by applicant): Neurons make synaptic connections with a precise specificity in order to assemble neural circuits. Although molecules that control initial axonal trajectories are relatively well understood, it is largely unknown how precise synaptic connections are formed within the target area. The goal of this proposal is to understand the molecular basis of synapse formation and synaptic specificity in the developing mouse spinal cord. The spinal reflex circuit in the spinal cord is an excellent model system to study synapse formation and synaptic specificity because of its relative simplicity and availability of abundant knowledge based on previous anatomical and electrophysiological studies. Cell bodies in the ventral gray matter are grouped into "motor neuron pools", which project axons to specific muscles. There are approximately fifty such motor neuron pools at the levels of the limbs in the mouse spinal cord. "Proprioceptive sensory neurons", which innervate these muscles with proprioceptive fibers, have their cell bodies in the dorsal root ganglia (DRG), and project axons into the spinal cord, which terminate and make synapses with the appropriate motor neuron pools. Our preliminary data strongly suggest that the semaphorin (sema) family of signaling ligands, and their receptors, the plexins, control synapse formation and synaptic specificity of the sensory-motor connections. First, of all semas and plexins, expression of only plexinA1, plexinD1, and sema6B is highly enriched in proprioceptive sensory neurons. Second, sema6D and its receptor plexinA1 are expressed by motor and proprioceptive sensory neurons when synaptogenesis is occurring. Third, plexinD1 is expressed by subsets of proprioceptive sensory neurons, while its ligand sema3E is expressed by subsets of motor neurons. We hypothesize that sema-plexin combinations contro l synapse formation and synaptic specificity in the developing spinal cord. The first aim will examine whether sema6D-plexinA1 signaling regulates synapse formation of sensory-motor connections. The second and third aims will examine if sema3E- plexinD1 and plexinA4-sema6B signaling control synaptic specificity of sensory-motor connections. We will address these issues by using a combination of anatomical, electrophysiological, behavioral, and in vitro analyses together with mouse genetics.