Planar Polarity Mechanisms in Mammalian Inner Ear Development

哺乳动物内耳发育中的平面极性机制

• 批准号: 10307536
• 负责人: MICHAEL R DEANS
• 金额: $ 32.41万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-25 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307536
• 关键词: Acceleration; Address; Anatomy; Apical; Articular Range of Motion; Auditory; Biological Assay; Birth; Candidate Disease Gene; Cell Differentiation process; Cell physiology; Cell surface; Chick; Detection; Development; Disease; Dorsal; Embryo; Ensure; Epithelial; Equilibrium; Event; Force of Gravity; Gene Expression; Gene Expression Profiling; Genes; Genetic Models; Genetic Transcription; Goals; Grant; Growth; Hair Cells; Impairment; Individual; Inner Hair Cells; Instruction; Kinocilium; Knockout Mice; Labyrinth; Lateral; Mechanics; Medial; Mediating; Molecular; Morphogenesis; Morphology; Motion; Movement; Mus; Neocortex; Organ; Otic Vesicle; Pathway interactions; Pattern; Peripheral; Physiological; Positioning Attribute; Posture; Process; Proteins; Regulator Genes; Research; Role; SHH gene; Saccule and Utricle; Saccule structure; Sensory; Sensory Hair; Sensory Receptors; Series; Shapes; Side; Signal Pathway; Signal Transduction; Spatial Distribution; Supporting Cell; System; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; Utricle structure; Utricular macula; Vestibular Hair Cells; WNT Signaling Pathway; base; body system; design; emx2 protein; equilibration disorder; expectation; experimental study; falls; gene function; gene regulatory network; hair cell regeneration; hedgehog signal transduction; inner ear development; macula; meetings; morphogens; mouse development; mouse model; mutant; overexpression; planar cell polarity; repaired; response; smoothened signaling pathway; sound; targeted treatment; transcription factor; transcriptome sequencing

Project Summary: In the vestibular system of the inner ear, motion is detected via the mechanical deflection of a bundle of stereocilia located at the top of sensory receptor hair cells. The bundle is morphologically and physiologically polarized because only movements of the bundle towards a lone kinocilium positioned at one side of the apical cell surface are able to produce excitatory responses to acceleration or gravity. Thus the range of motion that can be detected by an individual hair cell is determined by the polarized orientation of the stereociliary bundle. As a result, in order to generate a sensory representation encompassing the broadest possible range of motions, the utricle and saccule contain thousands of vestibular hair cells arranged in radiating arrays spanning a 360⁰ range of bundle orientations. This is achieved in part by dividing the hair cells between two groups separated by a Line of Polarity Reversal (LPR) that have opposing stereocilia bundle orientations and respond to motion in opposite directions. Our goal is to identify the cellular and molecular mechanisms that direct the development of planar polarity and underlie the formation of a sensory representation of gravity and acceleration in the vestibular maculae. This will be addressed through the course of the project using combinations of knockout and transgenic mouse models. Specifically, we will test a hypothesis developed during the first cycle of this grant that two key features organizing planar polarity are established earlier in development than previously expected, and within the otic vesicle. The first of these features is a polarity axis determined by the asymmetric distribution of core PCP proteins in hair cells and supporting cells. Since the formation of this axis is dependent upon the SHH signal transduction molecule Smoothened, we will undertake a series of experiments to determine the mechanisms by which SHH guides planar polarity, distinguishing between instructive and permissive roles. The second feature is a transcriptional boundary established by the transcription factor Emx2 that upon maturation is correlated with the position of the LPR and necessary for its formation. We propose that the emergence of an Emx2 boundary in the otic vesicle precedes formation of the LPR and therefore will identify mechanisms guiding Emx2 expression at early stages of development. Finally, we will determine the mechanisms that allow intercellular PCP signaling and transcriptional boundaries to be maintained throughout morphogenesis in order to understand how these early patterning events might be carried through to the mature sensory organs. Although focused on the development of vestibular planar polarity, we anticipate that this research will impact our understanding of auditory planar polarity as well as other organ systems that rely upon cellular polarization for growth or function.

项目总结： 在内耳的前庭系统中，运动是通过一束 立体纤毛位于感觉受体毛细胞的顶端。维管束在形态和生理上都是 极化是因为只有束向位于顶端一侧的孤立的动纤毛运动 细胞表面能够对加速度或重力产生兴奋性反应。因此，它的运动范围 是否能被单个毛细胞检测到是由立体纤毛束的极化方向决定的。 结果，为了产生包含最大可能范围的动作的感觉表示， 椭圆形和球囊包含数以千计的前庭毛细胞，它们排列成辐射阵列，横跨360⁰ 束方向的范围。这在一定程度上是通过将毛细胞分为两组来实现的 通过一条具有相反立体纤毛束方向的极性反转线(LPR)，并对 方向相反。 我们的目标是确定细胞和分子机制，指导平面极性和 在前庭黄斑形成重力和加速度的感觉表征。这 将在项目过程中使用基因敲除和转基因小鼠的组合来解决 模特们。具体地说，我们将测试在此拨款的第一个周期中开发的假设，即两个关键特征 有组织的平面极性在发育过程中比先前预期的更早建立，并在眼球内 水泡。这些特征中的第一个是由核心PCP的不对称分布确定的极轴 毛细胞和支持细胞中的蛋白质。由于该轴的形成取决于SHH信号 转导分子光滑后，我们将进行一系列实验，以确定其机制 SHH引导平面极性，区分指导性和允许性角色。第二个特点 是由转录因子Emx2建立的转录边界，成熟时与之相关 LPR的地位及其成立所必需的。我们认为Emx2边界的出现 在耳囊泡中的表达先于LPR的形成，因此将识别引导Emx2表达的机制 在发展的早期阶段。最后，我们将确定允许细胞间PCP信令的机制 并在整个形态发生过程中保持转录边界，以了解这些 早期的图案化事件可能会延续到成熟的感觉器官。尽管重点放在 前庭平面极化的发展，我们预计这项研究将影响我们对 听觉平面极化以及其他依赖细胞极化生长或功能的器官系统。