Genetic Regulation of Inner Ear Formation

内耳形成的遗传调控

• 批准号: 7086162
• 负责人: Monte Westerfield
• 金额: $ 44.82万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7086162
• 关键词: biological signal transduction; cell cell interaction; developmental genetics; developmental neurobiology; genetic mapping; genetic regulation; genetic screening; histogenesis; labyrinth; mutant; neurogenesis; point mutation; zebrafish

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand how cells are specified to form the ear and how these processes are affected in human hearing diseases. The inner ear arises from the otic placode that forms at the lateral edge of the neural plate adjacent to the hindbrain. Current theories suggest that inductive signals from neighboring tissues are specify formation of the placode. However, it is unknown how cells are allocated to the placode or how they respond to the inductive signals that trigger their differentiation into the ear. Previous studies identified and analyzed two sets of transcription factor pairs, DIx3b/4b and Sox9a/9b that interact in a genetic pathway to specify otic placode cells. This pathway is regulated by Fgf3/8 signals from the adjacent hindbrain. The proposed studies will test the hypothesis that DIx3b/4b function is required for cells to become competent to respond to Fgf3/8 inductive signaling and that Fgf3/8 directs convergence and epithelialization of otic precursor cells. The proposed studies will test whether DIx3b/4b is sufficient for otic competence by examining whether ectopic Fgf3/8 induces placodes only where DIx3b/4b is expressed and whether Fgf3/8 beads induce otic markers in cells that normally Inever contribute to the if cells forced to DIx3b/4b. To learn how DIx3b/4b is ear, these ectopic are express expression regulated by factors that control dorsoventral patterning; functions of Bmps, Chordin and their downstream targets will be altered. These experiments will provide a mechanistic understanding of how cells become competent to form the ear. The proposed studies will test whether Fgf3/8 directs the morphogenetic movements and epithelialization of otic precursor cell. They will test whether Fgf3/8 is required for these processes by examining embryos in which Fgf3/8 function is blocked by mutation and morpholino treatment. They will test whether Fgf3/8 is sufficient by learning whether Fgf3/8 beads induce ectopic convergence and/or epithelialization. These experiments will elucidate the link between induction and cellular morphogenesis and provide new insights into how cells are specified to form the ear. A genetic screen of mutant phenotypes will identify additional genes required for induction of the otic placode. These mutations will be characterized phenotypically with mosaic analyses and gene expression analyses in whole-mount embryos and with microarrays to learn how each gene functions, when function is critical and in which cells function is required. The mutations will be characterized genetically by mapping, by complementation testing with existing mutations, and by molecular cloning. This analysis will identify, on the basis of their functions, the critical genes required for formation of the otic placodes.

描述（由申请人提供）：本研究的长期目标是了解细胞如何被指定形成耳朵，以及这些过程如何在人类听力疾病中受到影响。内耳起源于与后脑相邻的神经板外侧边缘形成的耳基。目前的理论认为，来自邻近组织的感应信号指定了基板的形成。然而，尚不清楚细胞是如何分配到基因位的，也不知道它们是如何响应诱发它们分化到耳朵的感应信号的。先前的研究发现并分析了两组转录因子对，DIx3b/4b和Sox9a/9b，它们在遗传途径中相互作用以指定位点细胞。该通路受邻近后脑的Fgf3/8信号调控。这些研究将验证DIx3b/4b功能是细胞对Fgf3/8诱导信号做出反应所必需的假设，Fgf3/8指导耳部前体细胞的聚集和上皮化。