Mechanisms of PCP signaling in axon guidance and cochlear innervation

PCP信号在轴突引导和耳蜗神经支配中的机制

基本信息

批准号：
10207584
负责人：
MICHAEL R DEANS
金额：
$ 51.01万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10207584
关键词：
Acoustic Trauma Acoustics Affect Auditory Axon Binding Sites Cell membrane Cells ChIP-seq Characteristics Chemicals Cochlea Complex Cues Data Defect Development Developmental Process Dominant-Negative Mutation Ensure Eph Family Receptors Ephrin-A3 Ephrins Epithelial Event Gene Deletion Genetic Genetic Transcription Goals Growth Cones Hair Cells Image Inner Hair Cells Knock-out Knowledge Label Laboratories Ligands Membrane Minority Mus Natural regeneration Neurons Nociception Nociceptors Noise Organ of Corti Outer Hair Cells Pathology Pathway interactions Pattern Peripheral Phenotype Proteins Reporting Research Research Design Sensory Sensory Hair Signal Pathway Signal Transduction Site Supporting Cell Supporting Cell of Organ of Corti Synapses Testing Therapeutic Time Transgenes axon guidance base cell injury cell motility cell type conditional knockout conditional mutant deaf deafness experimental study mutant nerve supply neurodevelopment neuron development planar cell polarity preservation promoter receptor repaired sound spiral ganglion transcription factor transcriptome sequencing

项目摘要

Project Summary The cochlea is innervated by spiral ganglion neurons, which relay sound information from sensory hair cells to central auditory targets. Deafness due to acoustic trauma is associated with pathologies in both spiral ganglion neurons and the hair cells which they innervate, and an important aspect of repairing the deafened cochlea is coaxing spiral ganglion neurons to re-innervate their hair cell partners. It is generally anticipated that hair cell re- innervation will require the reactivation of developmental mechanisms. Therefore, understanding early developmental events is an important prerequisite for regeneration-based therapeutic strategies. A subset of spiral ganglion neurons has nociceptive characteristics and are thus equipped to detect acoustic trauma, which may be important for preserving function. These are the type II spiral ganglion neurons, which constitute a minority of cochlear afferents but innervate all outer hair cells. The development of type II neurons is unique and facilitates outer hair cell innervation because their peripheral axons project beyond the inner hair cells. An important component of cochlear innervation is how the type II spiral ganglion neurons subsequently make a distinct 90° turn towards the cochlear base to synapse with multiple outer hair cells. While many aspects of outer hair cell innervation are unknown, our laboratories have found that two signaling pathways, planar cell polarity (PCP) signaling and Eph/Ephrin signaling, are required for the 90° turn that directs the peripheral axon towards the cochlear base. A similar phenotype occurs with loss of the transcription factor Prox1 suggesting that a regulatory hierarchy controls cochlear innervation. The goal of this research is to establish the relationship between these two signaling pathways by examining each in detail and relative to each other. This includes experiments in Aim 1 to distinguish between alternative mechanisms in which PCP proteins pattern the organ of Corti prior to innervation or signal directly to the growth cone. Since the Ephrin receptor EphA7 is also required for axon turning, in Aim 2 we will determine if these pathways are linearly organized or if they are parallel and redundant signals with each promoting turning. Remarkably the EphA7 promoter contains putative Prox1 binding sites suggesting that these guidance mechanisms may be transcriptionally regulated. This hypothesis will be tested further in Aim 3. While these experiments are focused on developmental processes, we anticipate that these are events which must be reenacted during hair cell re-innervation and repair, and therefore the proposed research will advance therapies for repairing the deafened cochlea.

项目概要耳蜗由螺旋神经节神经元支配，螺旋神经节神经元将声音信息从感觉毛细胞传递到中枢听觉目标因声损伤而导致的耳聋与两个螺旋神经节的病变有关。神经元及其所支配的毛细胞，修复聋耳蜗的一个重要方面是诱导螺旋神经节神经元重新支配其毛细胞伴侣人们普遍预期毛细胞会重新受神经支配。神经支配需要重新激活发育机制，因此，尽早了解。发育事件是基于再生的治疗策略的重要先决条件。螺旋神经节神经元的一个子集具有伤害性特征，因此能够检测声音创伤，这对于保留功能可能很重要这些是 II 型螺旋神经节神经元，构成耳蜗传入神经的少数，但支配所有外毛细胞 II 型神经元的发育。是独特的，有助于外毛细胞神经支配，因为它们的外周轴突超出内毛耳蜗神经支配的一个重要组成部分是 II 型螺旋神经节神经元随后的分布。向耳蜗基部做出明显的 90° 转动，以与多个外毛细胞形成突触。外毛细胞神经支配的机制尚不清楚，我们的实验室发现了两条信号通路，平面细胞极性 (PCP) 信号传导和 Eph/Ephrin 信号传导是指导外周轴突的 90° 转动所必需的耳蜗基部的转录因子 Prox1 缺失时会出现类似的表型，这表明调节等级控制着耳蜗的神经支配。本研究的目的是通过检查来建立这两个信号通路之间的关系这包括目标 1 中区分替代方案的实验。 PCP 蛋白在神经支配之前对 Corti 器官进行模式化或直接向生长发出信号的机制由于 Ephrin 受体 EphA7 也是轴突转动所必需的，因此在目标 2 中我们将确定这些是否是轴突转动所必需的。路径是线性组织的，或者如果它们是平行且冗余的信号，则每个推动转弯。值得注意的是，EphA7 启动子包含假定的 Prox1 结合位点，表明这些指导这一假设将在目标 3 中得到进一步检验。实验的重点是发育过程，我们预计这些事件必须是在毛细胞重新神经支配和修复过程中重演，因此拟议的研究将推进治疗用于修复失聪的耳蜗。