ORPHAN NUCLEAR RECEPTOR COUP-TFI IN HEARING AND BALANCE

COUP-TF是一种孤儿核受体，被证明在控制几种生物的生长、发育、分化和动态平衡的不同方面发挥着重要作用。COUP-TF是基因表达的调节者，属于配体激活的转录因子的类固醇/甲状腺激素受体超家族。孤儿核受体基因的表达模式和时间决定了其靶组织和细胞内假定的配体信号通路的直接影响范围。COUP-TF在内耳器官发生过程中的空间和时间表达模式表明，它们可能在调节内耳功能形成的过程中发挥关键作用。事实上，Coup-TFI功能丧失突变体是聋人，在前庭的耳蜗和感觉斑点发育方面存在缺陷。这表明COUP-TFI是小鼠听力和平衡功能发育所必需的基因。为了更好地了解政变-TFI在听证和平衡方面的作用，这笔赠款将侧重于以下目标。1.通过对COUP-TFI在内耳结构以及脑干听觉和前庭核团发育和分化过程中的详细表达分析，表征了COUP-TFI突变体的缺陷。2.通过嵌合胚胎分析确定COUP-TFI的作用机制，以确定COUP-TFI在耳朵中是以细胞自主还是非自主的方式发挥作用。3.通过对耳蜗库和前庭cDNA库的消减文库筛选，确定内耳发育过程中COUP-TFI下游靶点。这些目标的完成将对内耳形态发生的这种新的调节机制提供实质性的见解，并将识别其信号通路中发育听力和平衡所需的基因。

The COUP-TFs are orphan nuclear receptors proven to play important roles in controlling diverse aspects of growth, development, differentiation and homeostasis in several organisms. The COUP-TFs are regulators of gene expression and belong to the steroid/thyroid hormone receptor superfamily of ligand-activated transcription factors. The pattern and timing of expression of an orphan nuclear receptor gene defines the sphere of direct influence of a putative ligand signaling pathway within its target tissues and cells. The spatial and temporal expression pattern of COUP-TFs during inner ear organogenesis suggest that they may play a critical role in regulating processes that lead to the formation of a functional inner ear. Indeed, COUP-TFI loss-of-function mutants are deaf, having defects in development of the cochlea and sensory maculae of the vestibule. This suggests that COUP-TFI is an essential gene for the development of both hearing and balance functions in the mouse. To better understand the role of COUP-TFI in hearing and balance this grant will focus on the following aims. 1. Characterize defects in COUP-TFI mutants with respect to a detailed expression analysis of COUP-TFI during development and differentiation of inner ear structure and the brainstem auditory and vestibular nuclei. 2. Determine the mechanism of COUP-TFI action using chimeric embryo analysis to ascertain whether COUP-TFI acts in a cell-autonomous or non-autonomous manner in the ear. 3. Identify COUP-TFI downstream targets during inner ear development by subtraction library screens of cochlea and vestibule cDNA libraries. The completion of these aims will provide substantial insight on this novel regulator of inner ear morphogenesis and will identify genes required in its signaling pathway for development of hearing and balance.