Origin and regulation of motor neuron identiy in hindbrain

脊椎动物的后脑对于控制一系列行为是必不可少的， 颅面肌肉系统对心血管和胃肠道系统的自主功能的影响。这些 行为依赖于运动神经元与它们沿头部沿着的外周目标的精确配准， 身体的前后（AP）轴。这种高度有序的关系起源于一个简单的胚胎体 运动神经元在单个菱形球内发育的计划，以及它们在相邻菱形球中的预期目标。 鳃弓组织一个主要的细胞贡献，这种运动神经元周围的目标关系， ; omes来自神经嵴细胞，一种来自背菱形节的限制性干细胞群 并迁移到周围的鳃弓组织中。施加在变化的物体上的位置信息 构成该运动神经元电路的细胞类型主要由Hox的AP限制性表达提供。 基因.然而，维持Hox基因AP限制性表达的机制及其在细胞内的表达， 控制来自后脑的神经元和神经嵴细胞分化的能力仍然存在 待定义。在第一个目标中，我们将使用菱球的遗传命运图来识别神经元细胞。 起源于神经嵴细胞的谱系及其可能受Hox基因调控。第二个目标， 我们将通过使用一个条件性的， 突变系统，以破坏Hox基因在祖细胞和有丝分裂后运动神经元中的功能， 腹神经管第三个目的是探讨Fgf信号通路对运动神经元的调控机制。 通过抑制后脑中Hox基因的活性来确定神经元亚型。后一个目标可能 揭示了一种机制，建立不同的运动神经元身份沿着整个AP轴的， 中枢神经系统了解分子和细胞决定因素有助于 运动神经元-外周靶回路的形成可以提供对受损神经元的治疗见解， 与运动神经元和神经传导相关的组织和疾病。

The vertebrate hindbrain is essential for controlling an array of behaviors, from voluntary movements of the craniofacial musculature to autonomic functions of the cardiovascular and gastrointestinal systems. These behaviors rely on the precise registration of motor neurons with their peripheral targets along the head and body's anterior-posterior (AP) axis. This highly ordered relationship originates from a simple embryonic body plan in which motor neurons develop within individual rhombomeres and their prospective targets in adjacent branchial arch tissues. A major cellular contribution to this motor neuron-peripheral target relationship ;omes from the neural crest cell, a restricted stem cell population that arises from the dorsal rhombomere and migrates into the surrounding branchial arch tissue. The positional information imposed upon the varied cell types constituting this motor neuron circuit is largely provided by the AP-restricted expression of the Hox genes. However, the mechanism that maintains the AP-restricted expression of the Hox genes and their ability to control the differentiation of the neurons derived from the hindbrain and the neural crest cell remain to be defined. In the first aim, we will use a genetic fate map of the rhombomeres to identify the neuronal lineages that arise from neural crest cells and their possible regulation by the Hox genes. In the second aim, we will address the role of Hox genes in neuronal differentiation through the use of a conditional mutagenesis system to disrupt Hox gene function among progenitors and postmitotic motor neurons in the ventral neural tube. In the third aim, we will explore a mechanism by which Fgf signaling regulates motor neuron-subtype identity by repressing the activity of the Hox genes in the hindbrain. The latter aim may reveal a mechanism that establishes the different motor neuron identities along the entire AP axis of the central nervous system. An understanding of the molecular and cellular determinants contributing to the formation of the motor neuron-peripheral target circuit may provide therapeutic insight into damaged nervous tissue and diseases associated with motor neurons and nerve conduction.