Developmental Mechanisms of Vestibular Maculae Patterning in Mouse

小鼠前庭黄斑模式的发育机制

• 批准号: 7993562
• 负责人: MICHAEL R DEANS
• 金额: $ 15.88万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7993562
• 关键词: Address; Alleles; Amino Acids; Animals; Apical; Architecture; Auditory; Behavioral; Cell Polarity; Cell surface; Cells; Cellular Assay; Characteristics; Cochlear duct; Cues; Cytoplasmic Tail; DNA Sequence; Detection; Development; Ear; Embryo; Epithelial Cells; Epithelium; Equilibrium; Event; Frequencies; Functional disorder; Genes; Genetic; Hair Cells; Hearing; Kinocilium; Knock-out; Knockout Mice; Labyrinth; Mechanics; Mediating; Morphogenesis; Motion; Movement; Mus; Mutant Strains Mice; Mutation; Neural Tube Defects; Organ of Corti; Outcome; Pattern; Phenotype; Physiological; Process; Production; Proteins; Reporting; Research Proposals; Saccule and Utricle; Sensory; Series; Signal Transduction; Staging; Stereocilium; Surface; Tail; Technology; Testing; Therapeutic; Tissues; Transgenic Organisms; Transmembrane Domain; Utricular macula; Vestibular Hair Cells; age related; base; critical period; deafness; design; ear sensory receptor; equilibration disorder; macula; meetings; motion sensitivity; mutant; novel; public health relevance; research study; response; sound

DESCRIPTION (provided by applicant): The senses of hearing and balance are mediated by the hair cells of the inner ear, sensory epithelial cells with specialized architectures optimized for the detection of movement. Hair cells detect motion via the mechanical deflection of a kinocilium and stereocilia bundle located at one edge of the apical cell surface. Only movements of the bundle towards the kinocilium generate an excitatory response. Consequently the proper polarization of the stereocilia bundle and coordination of bundle polarity between adjacent cells is necessary for accurate vestibular function. Auditory hair cells within the organ of Corti detect sound in a similar fashion and the bundle polarity of adjacent cells is also coordinated. This type of organization is called planar cell polarity (PCP) and has been described in a number of different tissues and species. Moreover, hair cells within the vestibular maculae are further organized into two groups with opposite bundle polarities patterned about an abrupt line of polarity reversal (LPR). This increases the range of detectable motion and sensitivity to motion in a single direction. However, despite the likely importance of stereocilia bundle polarity and hair cell patterning for vestibular function it is not known how bundle polarization is initiated and coordinated within the sensory epithelia. Within this research proposal the cellular mechanisms guiding the polarization of the stereocilia bundle and orientation of hair cells will be evaluated using a combination of transgenic, mutant and knockout mice. [The function of the essential polarity gene van gogh-like2 (vangl2) will be determined by analyzing hair cell PCP using a novel vangl2 knockout mouse (vangl2TMS). These results will be compared to the vangl2 mutant line looptail which has become a reference for inner ear PCP mutant analysis despite having semi-dominant phenotypic characteristics.] Next the cellular mechanism of Vangl2 function in coordinating bundle polarity between adjacent cells will be tested through the production and analysis of a vangl2 conditional knockout line (vangl2floxedATG) in which the polarity gene is deleted in a cell-specific manner. These experiments will determine whether polarity cues are propagated from cell to cell and whether vangl2 is necessary for initiating bundle polarity or maintaining bundle polarity during inner ear morphogenesis. In addition, other vangl2 mutations result in embryonic lethality and this will be avoided be generating ear-specific vangl2floxedATG conditional knockouts. These mice will enable a series of behavioral experiments to examine the effects of hair cell misorientation on vestibular and auditory function. PUBLIC HEALTH RELEVANCE: Project Narrative The proper morphogenesis and organization of specialized inner ear sensory receptors called hair cells is necessary for hearing and balance, and the loss of these cells is the primary basis of age-related deafness and balance disorders. This project is designed to determine how hair cells are oriented and patterned within the within the vestibular maculae of the utricle and saccule. Understanding these events should reveal the basis of some forms of vestibular dysfunction and will define critical parameters that must be met by therapeutic approaches that rely upon introducing replacement hair cells into the mature inner ear.

描述（由申请人提供）：听力和平衡的感觉是由内耳的毛细胞介导的，具有优化用于检测运动的专门体系结构的感觉上皮细胞。毛细胞通过位于顶端细胞表面的一个边缘的运动核和立体束的机械偏转来检测运动。只有束向运动核的运动产生兴奋反应。因此，对于准确的前庭功能，必须正确地对相邻细胞之间的束极性和束极性的协调。 Corti器官内的听觉毛细胞以相似的方式检测声音，并且相邻细胞的束极性也得到了协调。这种类型的组织称为平面细胞极性（PCP），已在许多不同的组织和物种中进行了描述。此外，前庭黄斑中的毛细胞被进一步组织成两组，其束极性相反，围绕着极性逆转（LPR）的突然线。这增加了在单个方向上可检测到的运动和对运动的敏感性的范围。然而，尽管立体束极性和毛细胞对前庭功能的重要性可能很重要，但尚不清楚如何在感觉上皮中启动和协调束极化。在这项研究建议中，将使用转基因，突变体和敲除小鼠的组合评估指导立体丝束的极化和毛细胞方向的细胞机制。 [基本极性基因van gogh like2（vangl2）的功能将通过使用新型的vangl2基因敲除小鼠（vangl2tms）分析毛细胞PCP来确定。这些结果将与vangl2突变线循环尾巴进行比较，尽管具有半主流表型的特征，但它已成为内耳PCP突变体分析的参考。细胞特异性的方式。这些实验将确定极性提示是否从细胞到细胞传播，以及在内耳形态发生过程中启动束极性或保持束极性的必要条件是必要的。此外，其他vangl2突变导致胚胎致死性，这将避免产生耳朵特异性的vangl2floxedatg条件敲除。这些小鼠将使一系列的行为实验能够检查毛细胞不良的影响对前庭和听觉功能的影响。 公共卫生相关性：项目叙事的适当形态发生和专门的内耳感觉受体称为毛细胞是听力和平衡所必需的，而这些细胞的丧失是与年龄相关的耳聋和平衡障碍的主要基础。该项目旨在确定毛细胞如何在尿素和肺泡的前庭斑点内定向和图案。了解这些事件应揭示某些形式的前庭功能障碍的基础，并将定义关键参数，这些参数必须通过依赖于将替换毛细胞引入成熟内耳的治疗方法来满足。