Molecular Basis For The Morphogenesis Of The Inner Ear

内耳形态发生的分子基础

• 批准号: 6965295
• 负责人: Doris Wu
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6965295
• 关键词: biological signal transduction; bone morphogenetic proteins; cell differentiation; chickens; cochlea; developmental genetics; developmental neurobiology; disease /disorder model; fibroblast growth factor; gene expression; gene mutation; gene targeting; genetically modified animals; head movements; hearing disorders; histogenesis; kidney disorder; laboratory mouse; labyrinth; semicircular duct

Our major accomplishments this year are in the following areas: 1) Analyses of inner ears in Pax2 knockout mice Mutations in the PAX2 gene cause renal coloboma syndrome in humans that is associated with kidney abnormalities, optic nerve colobomas and mild sensorineural deafness. Pax2 knockout mice serve as a good animal model for the study of this syndrome since these mice display developmental defects in the same organs as human patients. We show that the overall development, outgrowth, and differentiation of the cochlear duct are affected in the Pax2 knockout mice. Even though the organ of Corti is poorly developed, sensory hair cells do form in the mouse mutants. These results raise the possibility that the etiology of hearing loss in renal coloboma syndrome may not be due to deficits within sensory hair cells but due to disruption of other cochlear functions. 2) Roles of FGF and BMP2 in the development of the apparatus that detects head movements The ability to detect angular head movements in vertebrates lies in the three semicircular canals and their sensory tissues, the cristae. The molecular mechanisms involved in the formation of this apparatus are not known. Using gain- and loss-of-function experiments in chicken, we show that FGFs in the presumptive cristae are important for crista formation. In addition, FGF emanating from the sensory regions promote canal formation by up-regulating Bmp2 expression in the canal genesis zone. Our results provide the first molecular evidence whereby sensory organs direct the development of their associated, non-sensory components, the semi-circular canals.

今年我们的主要成绩有以下几个方面： 1) Pax2基因敲除小鼠内耳分析 PAX2 基因突变会导致人类肾缺损综合征，该综合征与肾脏异常、视神经缺损和轻度感音神经性耳聋相关。 Pax2 基因敲除小鼠是研究这种综合征的良好动物模型，因为这些小鼠与人类患者的相同器官表现出发育缺陷。我们发现 Pax2 敲除小鼠的耳蜗管的整体发育、生长和分化受到影响。尽管柯蒂氏器官发育不良，但突变小鼠中确实形成了感觉毛细胞。这些结果提出了一种可能性，即肾缺损综合征中听力损失的病因可能不是由于感觉毛细胞内的缺陷，而是由于其他耳蜗功能的破坏。 2) FGF和BMP2在头部运动检测装置开发中的作用 检测脊椎动物头部有角度运动的能力在于三个半规管及其感觉组织——嵴。该装置形成所涉及的分子机制尚不清楚。通过对鸡的功能获得和丧失实验，我们发现假定嵴中的 FGF 对于嵴形成很重要。此外，感觉区发出的 FGF 通过上调根管发生区的 Bmp2 表达来促进根管形成。我们的研究结果提供了第一个分子证据，据此，感觉器官指导其相关的非感觉部分（半规管）的发育。