Genetic Dissection of Vangl2-Dependent Axon Guidance in the Developing Cochlea

发育中耳蜗中 Vangl2 依赖的轴突引导的遗传解剖

基本信息

批准号：
9385989
负责人：
MICHAEL R DEANS
金额：
$ 22.73万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9385989
关键词：
Acoustic Trauma Address Afferent Neurons Alpha Cell Anatomy Auditory Axon Biological Assay Cells Cochlea Complex Contralateral Defect Development Developmental Process Dissection Embryo Environment Epithelium Event Feedback Foundations Frequencies Gene Deletion Genes Genetic Genetic Recombination Goals Growth Cones Hair Cells Head Hearing Individual Inner Hair Cells Knock-out Laboratories Labyrinth Medial Mediating Molecular Morphology Mutation Natural regeneration Neonatal Neural tube Neurons Noise One-Step dentin bonding system Organ of Corti Outer Hair Cells Pathology Pathway interactions Pattern Peripheral Phenotype Phosphorylation Process Property Protein Tyrosine Kinase Proteins Radial Receptor Protein-Tyrosine Kinases Receptor Signaling Reporting Research Research Project Grants Sensory Sensory Receptors Series Signal Pathway Signal Transduction Signal Transduction Pathway Site Speech Discrimination Stereotyping Synapses System Therapeutic WNT Signaling Pathway axon growth axon guidance base beta catenin deafness design expectation experimental study hindbrain migration morphogens mutant nerve supply neuron development neuroprotection planar cell polarity receptor receptor function repaired response sensory input sound spiral ganglion

项目摘要

The cochlea is innervated by the bipolar sensory neurons of the spiral ganglia that relay sound information from sensory receptor 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 involve similar cellular and molecular mechanisms to those guiding nascent hair cell innervation. Therefore, understanding all aspects of spiral ganglion development and hair cell innervation are important prerequisites of regeneration-based therapeutic strategies. A subset of neurons in the spiral ganglion is dedicated to a fundamentally important feedback circuit that provides neuroprotection in extreme noise and facilitates hearing and speech discrimination in background noise. This circuit is dependent on the Type2 spiral ganglion neurons (SGN2) that innervate the outer hair cells. The morphological development of SGN2s is unique because their peripheral axon projects beyond the inner hair cells before making a distinct 90° turn towards the base of the cochlea in order to synapse with 8 to 10 outer hair cells. While many aspects of SGN2 development and outer hair cell innervation are not known, our laboratory has found evidence that the planar cell polarity protein Vangl2 contributes to at least one step in this process; the turning event that directs the SGN2 peripheral axon to the base of the cochlea. The goal of this Exploratory/Developmental Research grant is to establish two basic properties of Vangl2 function during SGN2 peripheral axon turning with the expectation that this will form the foundation of a larger, independent line of research addressing spiral ganglion development. The first is to distinguish between autonomous and non-cell autonomous sites of Vangl2 function in the peripheral axon growth cone or organ of Corti. This will be accomplished using a vangl2 conditional knockout line previously generated by the lab in combination with Cre lines selected to spatially restrict vangl2 gene deletion. The second is to assay the relative contribution of two alternative non-canonical Wnt receptors and signaling pathways that have been demonstrated to function upstream of Vangl2 in other contexts. This will be established through genetic interaction assays based upon the hypothesis that if Vangl2 and an upstream receptor function in the same pathway, then removing both will enhance SGN2 turning phenotypes. While these experiments are focused on developmental processes guiding axon pathfinding and target cell innervation we anticipate that these events must be recapitulated during hair cell re-innervation and repair, and therefore the proposed research will advance therapies for repairing the deafened cochlea.

耳蜗由螺旋神经节的双相神经元从感觉式呈现为中心，而聋哑人的教练是诱使神经元重新发明头发的脱发细胞重新融合到指导新生毛细胞神经的那些类似的分子机制。电路依赖于支配外毛细胞的长时间神经节神经元（SGN2），因为它们的周围轴突在内毛细胞之外发射，然后将90°朝向耳蜗的底部，以便用8至10个外毛突触细胞在SGN2外围轴突中，探索性/发展研究具有vangl2函数的两个基本特性，该轴突的转向是形成了较大的，独立的重塑螺旋神经节发育的形成vangl2在外围轴突生长锥中的功能或皮尔蒂的器官。在其他情况下，如果vangl2和上游的受体在同一途径中，则在其他情况下将建立遗传相互作用。神经支配我们预计必须在毛细胞修复期间概括这些事件，使他对耳蜗聋。