Origin and regulation of motor neuron identiy in hindbrain

后脑运动神经元身份的起源和调节

基本信息

批准号：
8381129
负责人：
Gary O Gaufo
金额：
$ 24.74万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8381129
关键词：
Address Alleles Anterior Axon Behavior Branchial arch structure Cardiovascular system Cells Collaborations Defect Development Disease Dorsal Ectopic Expression Embryo Evaluation Face Facial nerve structure Ganglia Gene Expression Genes Genetic Germ-Line Mutation Goals Head Individual Knock-out Maps Mediating Mesoderm Molecular Moon Motor Neurons Movement Mus Mutagenesis Nerve Tissue Neural Conduction Neural Crest Neural Crest Cell Neural tube Neuraxis Neurobiology Neuronal Differentiation Neurons Pattern Peripheral Phenotype Process Regulation Repression Role Signal Transduction Signaling Molecule Staging System Testing Texas Therapeutic Tissues Universities Visceral base cell type cholinergic craniofacial gain of function gastrointestinal system gene function gene repression hindbrain insight member migration mutant neuron development novel progenitor programs prospective research study stem cell population tool transcription factor

项目摘要

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.

脊椎动物后脑对于控制一系列行为至关重要心血管和胃肠道系统的自主功能的颅面肌肉。这些行为依赖于运动神经元的精确注册，其头部沿头部的周围靶标身体的前后轴（AP）轴。这种高度有序的关系起源于一个简单的胚胎身体计划在单个菱形内部运动神经元及其前瞻性目标中发展的计划分支拱形组织。对该运动神经元 - 外围靶关系的主要细胞贡献 ;来自神经rest细胞，这是由背侧菱形产生的受限干细胞种群并迁移到周围的分支拱形组织中。施加在各种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限制表达提供基因。但是，保持HOX基因及其AP限制表达的机制及其能够控制源自后脑和神经rest细胞的神经元的分化能力定义。在第一个目标中，我们将使用菱形的遗传命运图来识别神经元由神经rest细胞及其可能由HOX基因调节产生的谱系。在第二个目标中我们将通过使用条件来解决HOX基因在神经元分化中的作用诱变系统破坏祖细胞和有丝分裂运动神经元之间HOX基因功能腹神经管。在第三个目标中，我们将探索一种机制，通过该机制，FGF信号调节电动机神经元 - 培养基的身份通过抑制后脑中HOX基因的活性。后一个目标可能揭示一种机制，该机制在整个AP轴上建立了不同的运动神经元身份中枢神经系统。对有助于促成的分子和细胞决定因素的理解运动神经元 - 外周靶回路的形成可能会提供治疗性的洞察力，以了解受损的神经与运动神经元和神经传导相关的组织和疾病。