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，从 头面部肌肉对心血管和胃肠系统的自主神经功能的影响。这些 行为依赖于运动神经元与它们的外周目标沿头部和 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身体 运动神经元在单个菱形核内发育的计划及其邻近的预期靶点 颧弓组织。细胞对这种运动神经元-外周靶点关系的主要贡献 ；来自神经脊细胞的OMES，这是一种起源于背菱形核的限制性干细胞群体 并迁移到周围的颧弓组织中。施加在不同对象上的位置信息 构成这个运动神经元回路的细胞类型在很大程度上是由Hox的AP限制性表达提供的 基因。然而，维持Hox基因和它们的AP限制性表达的机制 控制来自后脑和神经脊细胞的神经元分化的能力仍然存在 待定。在第一个目标中，我们将使用菱形核的遗传命运图来识别神经元 起源于神经脊细胞的谱系以及它们可能受HOX基因的调控。在第二个目标中， 我们将通过使用条件性基因来解决HOX基因在神经元分化中的作用 基因突变系统破坏大鼠神经元祖细胞和有丝分裂后运动神经元的HOX基因功能 腹侧神经管。在第三个目标中，我们将探索成纤维细胞生长因子信号调节运动的机制 通过抑制后脑中HOX基因的活性来识别神经元亚型。后一目标可能 揭示了一种机制，它建立了沿着整个AP轴的不同运动神经元身份 中枢神经系统。对分子和细胞决定因素的理解 运动神经元-外周靶点回路的形成可能为受损的神经提供治疗洞察力 与运动神经元和神经传导有关的组织和疾病。

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.