Fate acquisition and function of type I and II vestibular hair cells in mammals

项目摘要 我们的平衡感依赖于前庭毛细胞，它可以检测头部的运动。哺乳动物有 I型和II型前庭毛细胞，具有不同的形态、分子和生理特征 传入神经的特性和独特形式。在成年哺乳动物中，只有II型毛细胞在 正常情况下和损坏后。我们既不了解I型和II型毛细胞的具体功能，也不了解 它们编码的信息类型，并通过前庭神经发送到大脑。此外，人们对此知之甚少。 关于控制每种毛细胞类型的产生和维持的机制。这一知识是 对于开发通过细胞再生恢复前庭功能的有效疗法至关重要， 移植，或神经刺激(前庭植入)。 在成熟的哺乳动物中，转录因子sox2在II型毛细胞中表达，但在I型毛细胞中不表达。 细胞。我们最近有一个令人兴奋的发现：成人II型毛细胞中SOX2基因的条件性缺失 小鼠使它们获得I型毛细胞的形态和分子特征，并建立花萼 典型的I型毛细胞的神经支配。这种转分化导致了显著更高的比例 I型：II型毛细胞分布于前庭上皮各区。 在这项提案中，一个拥有不同但高度关联的专业领域的调查团队将利用 我们新发现的诱导成熟哺乳动物前庭毛细胞转分化的能力可以促进我们的 了解I型和II型毛细胞如何获得和保持其独特的特性，以及每根毛发是如何 细胞类型对前庭功能有贡献。在目标1中，我们将进一步测试Sox2在成人II型中是否功能丧失 毛细胞使它们转化为I型毛细胞，我们将确定Sox2在成年人中是否功能增强 I型毛细胞诱导其转分化为II型毛细胞。我们改变第一类和第二类的比例的能力 成年小鼠的毛细胞提供了一个机会来解决长期存在的关于功能 这些细胞类型之间的差异。在目标2中，我们将评估每种毛细胞类型的功能贡献 通过SOX2条件基因敲除或SOX2条件基因敲除改变I型：II型比例，从而影响传入神经活动和动物行为 异类表达。I型和II型特异性的建立依赖于精确的基因表达模式 反映在每种细胞类型的独特染色质状态中。在目标3中，我们将分析细胞的染色质状态 正常I型和II型毛细胞，并研究这些染色质状态在转分化过程中的变化 在成年后操纵SOX2。 好了！

Project Abstract Our sense of balance relies on vestibular hair cells, which detect head movements. Mammals have type I and type II vestibular hair cells, which have distinct morphological, molecular, and physiological properties and unique forms of afferent innervation. Only type II hair cells are replaced in adult mammals under normal conditions and after damage. We do not understand the specific functions of type I and II hair cells nor the types of information they encode and send to the brain via the vestibular nerve. Furthermore, little is known about the mechanisms controlling the production and maintenance of each hair cell type. This knowledge is critical for developing effective therapies to restore vestibular function, through cell regeneration, transplantation, or nerve stimulation (vestibular implants). In mature mammals, the transcription factor Sox2 is expressed in type II hair cells but not in type I hair cells. We recently made the exciting discovery that conditional deletion of Sox2 from type II hair cells of adult mice causes them to acquire morphological and molecular features of type I hair cells and to establish calyx innervation typical of type I hair cells. This transdifferentiation resulted in a significantly higher proportion of type I:II hair cells in all zones of the vestibular epithelia. In this proposal, a team of investigators with distinct but highly connected areas of expertise will exploit our new-found ability to induce vestibular hair cell transdifferentiation in mature mammals to advance our understanding of how type I and II hair cells acquire and maintain their unique properties and how each hair cell type contributes to vestibular function. In Aim 1, we will further test if Sox2 loss-of-function in adult type II hair cells causes them to convert into type I hair cells, and we will determine if Sox2 gain-of-function in adult type I hair cells induces their transdifferentiation to type II hair cells. Our ability to alter proportions of type I and II hair cells in adult mice provides an opportunity to address long-standing questions regarding the functional differences between these cell types. In Aim 2, we will assess the functional contributions of each hair cell type to afferent nerve activity and to animal behavior by altering the type I:II ratio via Sox2 conditional knock-out or ectopic expression. The establishment of type I and II specificity relies on a precise pattern of gene expression reflected in the unique chromatin state of each cell type. In Aim 3, we will analyze the state of chromatin of normal type I versus type II hair cells and study how these chromatin states change during transdifferentiation after Sox2 manipulation in adulthood. !