ORPHAN NUCLEAR RECEPTOR COUP-TFI IN HEARING AND BALANCE

听力和平衡中的孤儿核受体 CoUP-TFI

• 批准号: 6335724
• 负责人: Fred A Pereira
• 金额: $ 10万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6335724
• 关键词: balance; cochlea; developmental genetics; embryo /fetus; genetic library; growth /development; hearing; histogenesis; laboratory mouse; labyrinth; mammalian embryology; nuclear receptors; transcription factor; vestibular apparatus

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.

COUP-TF是孤儿核受体，被证明在控制几种生物体的生长、发育、分化和稳态的各个方面中发挥重要作用。COUP-TF是基因表达的调节因子，属于配体激活转录因子的类固醇/甲状腺激素受体超家族。孤儿核受体基因表达的模式和时间决定了其靶组织和细胞内推定配体信号传导途径的直接影响范围。COUP-TF在内耳器官发生过程中的时空表达模式表明，它们可能在调节导致功能性内耳形成的过程中发挥关键作用。事实上，COUP-TFI功能丧失突变体是耳聋的，耳蜗和前庭感觉斑的发育存在缺陷。这表明COUP-TFI是小鼠听力和平衡功能发育的必需基因。为了更好地了解COUP-TFI在听力和平衡方面的作用，这笔拨款将重点关注以下目标。1.描述COUP-TFI突变体在内耳结构和脑干听觉和前庭核的发育和分化过程中COUP-TFI的详细表达分析方面的缺陷。2.使用嵌合胚胎分析确定COUP-TFI作用的机制，以确定COUP-TFI在耳中是以细胞自主还是非自主方式起作用。3.通过耳蜗和前庭cDNA文库的消减文库筛选鉴定内耳发育过程中COUP-TFI下游靶标。这些目标的完成将为这种内耳形态发生的新型调节器提供实质性的见解，并将确定其信号通路中所需的基因，以促进听力和平衡的发展。