Sensory Organ Formation in the Inner Ear

 描述(申请人提供)：很大比例的耳聋和前庭疾病是由内耳包括毛发在内的关键细胞类型的丧失或功能障碍引起的 细胞、支持细胞和耳蜗前庭神经元。因此，为了治疗多种形式的内耳功能障碍，彻底了解这些细胞类型是如何形成的，是设计细胞再生或替代疗法的必要前提。谱系研究表明，这些细胞类型可以起源于共同的祖细胞。因此，再生或替换这些细胞类型的一种方法是通过产生这些多能祖细胞。这一研究计划的长期目标是了解控制神经感觉前体细胞规格的分子机制，以及控制这些前体细胞产生不同类型细胞的因素。虽然我们开始了解一些在感觉前体细胞谱系中很重要的因素，但仍然有许多基本的问题没有得到回答，包括感觉前体细胞是如何以及何时产生的。SRY-box转录因子SOX2是感觉前体细胞发育所必需的因子。对小鼠的功能丧失研究表明，SOX2是感觉祖细胞发育的关键因素，因为SOX2的缺失导致内耳上皮中所有毛细胞和支持细胞完全缺失。然而，我们仍然对SOX2如何以及何时在这些重要的前体细胞的发育中发挥作用知之甚少。在这项提案中，我们将重点了解SOX2如何作用于产生感觉区。具体地说，为了定义SOX2功能的空间和时间要求，我们将使用新产生的可诱导的小鼠Cre等位基因来定位表达SOX2的细胞并执行定时删除实验(目标I和II)。在目标III中，我们将研究SOX2是否能够在出生后和成年内耳产生异位感觉区。最后，我们将通过救援实验来测试JAG1介导的Notch信号是否作用于SOX2的上游(目标IV)。Notch信号在感觉前体细胞的产生中也是关键的。总之，这些实验将揭示SOX2功能的基本方面，并进一步阐明SOX2通过产生感觉前体细胞来再生或取代耳朵中的关键细胞类型的潜力。

 DESCRIPTION (provided by applicant): A large proportion of deafness and vestibular disorders are caused by loss or dysfunction of critical cell types in the inner ear, including hair cells, supporting cells and cochleovestibular neurons. Thus, in order to treat many forms of inner ear dysfunction, a thorough understanding of how these cell types form is a necessary prerequisite for designing cell regeneration or replacement therapies. Lineage studies have demonstrated that these cell types can arise from a common progenitor. Thus, one approach to regenerating or replacing these cell types is through the generation of these multipotent progenitors. The long-term goal of this research program is to understand the molecular mechanisms that control specification of the neurosensory progenitors, as well as the factors controlling the generation of the different cell types arising from these progenitors. Although we are beginning to understand some of the factors that are important in the lineage of the sensory progenitors, there are still many fundamental questions that remain unanswered, including how and when the sensory progenitors are generated. The SRY-box transcription factor SOX2 is an essential factor for sensory progenitor development. Loss of function studies in the mouse have shown that SOX2 is a critical factor for development of the sensory progenitors, as deletion of SOX2 leads to complete absence of all hair cells and supporting cells in the inner ear epithelium. However, we still have little understanding of how and when SOX2 acts in the development of these important progenitors. In this proposal we will focus on understanding how SOX2 acts to generate the sensory regions. Specifically, to define the spatial and temporal requirements for SOX2 function, we will use a newly-generated inducible mouse Cre allele to fate map SOX2-expressing cells and perform timed-deletion experiments (Aim I and II). In Aim III we will investigate whether SOX2 is capable of producing ectopic sensory regions in the postnatal and adult inner ear. Finally, we will test whether JAG1- mediated Notch signaling, which is also critical in the generation of the sensory progenitors, acts upstream of SOX2 by performing rescue experiments (Aim IV). Together, these experiments will reveal fundamental aspects of SOX2 function and further elucidate the potential of SOX2 in regenerating or replacing critical cell types in the ear through generation of the sensory progenitors.