Genetic Control of Topographic Map Formation in the Development of Spinal Circuits

控制哺乳动物重要行为的神经回路，如运动和呼吸，依赖于 运动神经元（MN）与靶细胞建立中枢和中枢选择性连接的能力 外围的支配特定肌肉目标的运动神经元由以下大家族指定： 染色体排列的Hox转录因子。Hox基因功能的一个关键方面是分离马达， 神经元分为拓扑组织柱状和池亚型。虽然有人建议， MN的躯体定位组织进化为促进越来越复杂的肢体的激活 肌肉组织，很大程度上是未知的MN如何集群成列，以及MN的位置在塑造中起着什么作用 运动神经网络内连接的特异性。在本提案中，我们将研究Pbx的功能 基因，Hox蛋白的必要辅助因子，在MN地形图的形成和发育中的作用。 电机电路。本研究的主要目的是：1）评估Pbx基因在组织中的作用 和脊髓运动神经元的连接，2）以确定运动神经元 地形学组织，和3）定义MN位置和身份在脊髓回路组装中的作用。在 目的1我们将使用遗传操作和组织学方法来确定Pbx基因在MN分化中的功能。 测定。在Aim2中，我们将确定MN中Pbx蛋白的靶点，并评估其功能和机制 监管。在Aim3中，我们将评估运动神经元的位置和身份如何影响 与突触前中间神经元群体的联系。通过深入了解运动神经元 规范程序在哺乳动物中，这些研究应该提供基本的见解机制， 组装哪些电机电路。

The neural circuits governing behaviors vital to mammals, such as locomotion and respiration, rely on the ability of motor neurons (MNs) to establish selective connections with target cells both centrally and peripherally. Motor neurons innervating specific muscle targets are specified by the large family of chromosomally arrayed Hox transcription factors. A key aspect of Hox gene function is to segregate motor neurons into topographically organized columnar and pool subtypes. While it has been suggested the somatotopic organization of MNs evolved to facilitate the activation of an increasingly more complex limb musculature, it is largely unknown how MNs cluster into columns, and what role MN position plays in shaping the specificity of connections within motor networks. In this proposal we will investigate the function of Pbx genes, essential co-factors of Hox proteins, in the formation of MN topographic maps and in the development of motor circuits. The major goals of this proposal are to: 1) to assess the role of Pbx genes in the organization and connectivity of spinal motor neurons, 2) to determine the mechanisms through which motor neurons are topographically organized, and 3) to define the role of MN position and identity in spinal circuit assembly. In Aim1 we will define the function of Pbx genes in MN differentiation using genetic manipulations and histological assays. In Aim2 we will identity the targets of Pbx proteins in MNs, and assess their function and mechanisms of regulation. In Aim3 we will assess how motor neuron position and identity influences the specificity of connections with presynaptic interneuron populations. By building off our in depth knowledge of motor neuron specification programs in mammals, these studies should provide basic insights into the mechanisms through which motor circuits are assembled.