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.

项目摘要耳蜗由螺旋神经节神经元支配，该神经元将声音信息从感觉毛细胞传递到中央听觉目标。由于声学创伤引起的耳聋与两种螺旋神经节的病理有关神经元及其支配的毛细胞以及修复破坏的耳蜗的重要方面是哄骗螺旋神经元神经元重新启动其毛细胞伴侣。人们普遍认为，毛细胞会重新神经需要重新激活发育机制。因此，尽早理解发展事件是基于再生治疗策略的重要先决条件。螺旋神经神经元的一部分具有伤害性特征，因此等效于检测声学创伤，这对于保存功能可能很重要。这些是II型螺旋神经神经元，构成了少数人工耳蜗的传入，但支配了所有外毛细胞。 II型神经元的发展是独一无二的，促进了外部毛孔神经支配细胞。人工耳蜗神经的重要组成部分是II型螺旋神经神经元如何随后如何使90°转向人工耳蜗，以与多个外毛细胞突触。而许多方面外毛细胞神经支配的神经未知，我们的实验室发现两个信号通路，平面电池极性（PCP）信号传导和EPH/EPHRIN信号传导是指向周围轴突的90°转弯所必需的朝向人工耳蜗。丢失转录因子Prox1也会发生类似的表型，这表明监管层次结构控制着人工耳蜗神经。这项研究的目的是通过检查这两个信号途径之间的关系彼此详细介绍。这包括AIM 1中的实验以区分替代方案 PCP蛋白在神经支配之前或直接发信号的PCP蛋白质的机制由于轴突转动也需要晶状体蛋白受体epha7，因此在AIM 2中，我们将确定这些是否是否途径是线性组织的，或者如果它们是平行的，并且冗余信号与每个促进转动。值得注意的是，epha7启动子包含假定的Prox1结合位点，表明这些指导机制可能会受到转录调节。该假设将在AIM 3中进一步检验。实验专注于发展过程，我们预计这些事件必须是在毛细胞重新发作和修复过程中重新成熟，因此拟议的研究将进取疗法用于修理被破坏的耳蜗。