Mechanism and Functional Significance of Polarity Reversal in Mechanosensory Organs

机械感觉器官极性反转的机制和功能意义

• 批准号: 10530662
• 负责人: Kathleen E Cullen
• 金额: $ 69.17万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10530662
• 关键词: Ablation; Acceleration; Address; Adopted; Adult; Affect; Age; Anatomy; Animal Model; Anterior; Auditory; Automobile Driving; Behavior; Birth; Calcium; Cell Differentiation process; Cell Maturation; Cell Polarity; Cell physiology; Cells; Cessation of life; Compensation; Complex; Data; Development; Disease; Dizziness; Electrophysiology (science); Ensure; Epithelial Cells; Epithelium; Equilibrium; Evoked Potentials; Eye Movements; Fishes; Frequencies; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic; Genetic Epistasis; Goals; Gravity Perception; Hair; Hair Cells; Head; Head Movements; Hearing; Heterotrimeric GTP-Binding Proteins; Homologous Gene; Image; Impairment; Intercellular Junctions; Ion Channel; Labyrinth; Lateral; Measures; Mediating; Modality; Molecular; Motion; Mus; Mutant Strains Mice; Organ; Orphan; Pathway interactions; Pattern; Pertussis Toxin; Phenocopy; Physiology; Population; Positioning Attribute; Process; Proteins; Research; Role; Saccule and Utricle; Saccule structure; Sense Organs; Sensory; Shapes; Signal Transduction; Sister; Stimulus; System; Testing; Time; Utricle structure; Vertebrates; Vision; Visual; Water Movements; Work; Zebrafish; afferent nerve; behavior test; emx2 protein; gamma-Aminobutyric Acid; gaze; innovation; insight; interest; kinetosome; lateral line; macula; mechanical stimulus; mechanotransduction; molecular marker; mutant; nerve supply; neuromast; planar cell polarity; prevent; programs; public health relevance; receptor; receptor function; regional difference; response; signal processing; therapy design; transcription factor; vestibulo-ocular reflex; virtual; water flow

PROJECT SUMMARY/ABSTRACT Vestibular disorders affect as many as 35% of adults past age 40. Studies of the vestibular inner ear have yielded important insights into how we process and compensate for head motion including the existence of parallel channels of information in the afferent nerve. In macular organs, for example, two populations of hair cells adopt opposite planar orientations of their hair bundles and thus opposite responses to head movements. This highly conserved bidirectional organization was first described in neuromasts, the lateral line organs sensing water movements in fish, but the genetic program implementing this reversal during development is only starting to be deciphered. Consequently, ablation studies to reveal the importance of reversal for vestibular function have not been possible until recently. Here we propose to address this question by investigating the consequences of inactivating an orphan G protein coupled receptor (GPCRx), implicated by our preliminary data in orientation reversal in mouse hair cell epithelia. Based on our preliminary data, we suggest that mouse GPCRx functions downstream of the transcription factor EMX2 and upstream of the heterotrimeric G protein Gi to reverse a ground state of polarity established by planar cell polarity proteins. We will test this hypothesis and also use the GPCRx mutant as an animal model to pinpoint how polarity reversal shapes macular organ responses and downstream effects on vestibular behaviors. To reach these goals, we will: 1) Use genetics to determine how GPCRx instructs reversal at the molecular level, solving its epistatic relationship to EMX2, Gi and planar cell polarity proteins in mice, and use zebrafish to test whether GPCRx-Gi is a conserved effector pathway for reversal. 2) Use molecular markers, electrophysiology and calcium imaging to resolve hair cell maturation and function in absence of polarity reversal. 3) Determine how polarity reversal affects afferents' organization and function, with afferent recordings, as well as overall vestibular function using behavioral tests. Our coherent body of preliminary evidence ensures the feasibility and the high interest of the project, and our focus on a virtually unstudied receptor protein guarantees innovation. The multi-PI team is ideally suited to address complementary questions in both the mouse and zebrafish acoustico-lateralis systems. We anticipate that this collaborative effort will be decisive towards solving the mechanism of hair cell orientation reversal, its conservation across vertebrates and its significance for mammalian vestibular physiology. Thorough understanding of polarity reversal will help interpret and design treatments for vestibular dysfunctions.

项目总结/文摘