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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：
10430177
负责人：
MICHAEL R DEANS
金额：
$ 44.29万
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/10430177
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.

项目总结