Morphogenetic signaling by retinoic acid and its regulation during inner ear development

视黄酸的形态发生信号及其在内耳发育过程中的调节

• 批准号: 42247102
• 负责人: Professor Dr. Gerrit Begemann
• 金额: --
• 依托单位: Lehrstuhl für Tierphysiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/42247102?language=en
• 关键词: Morphogenetic; signaling; retinoic; acid; its; Morphogenetic; signaling; retinoic; acid; its

Vertebrate inner ear development is sensitive to alterations in retinoic acid (RA) signaling, but the morphogenetic processes that are controlled by RA and its molecular targets are largely unexplored. Whereas mammals co-express three retinaldehyde-dehydrogenases within the inner ear, only Aldh1a3 and Aldh1a2 are present in the zebrafish developing inner ear and in flanking tissues, respectively. It is thus feasible to accomplish a straightforward genetic analysis of RA function in the zebrafish otic vesicle. Our goals are threefold: 1) We will use genetic and chemical genetic methods to examine the hypothesis that RA signaling patterns epithelial projections in the inner ear and is required for the formation of the otic capsule; 2) In a microarray analysis we have identified candidate target genes that are up- and down-regulated by RA signaling; we will characterize their expression profiles and RA-sensitivity in the inner ear and will examine their function by gene knockdown; 3) To advance the visualization and to dissect the cellular dynamics of inner ear morphogenesis, we will develop transgenic zebrafish lines that recapitulate RA-mediated gene activation and the dynamics of RA synthesis within the inner ear in vivo. Together, the proposed studies will unravel the roles of RA-mediated control of gene activity and will allow us to associate molecular genetic interactions with morphological change in the developing inner ear.

脊椎动物内耳的发育对视黄酸（RA）信号的改变敏感，但是由RA控制的形态发生过程及其分子靶标在很大程度上没有探索。哺乳动物在内耳内共表达三种视网膜甲醛 - 脱水酶，但分别存在于斑马鱼内耳和侧面组织中的aldh1a3和aldh1a2。因此，可以对斑马鱼囊泡中的RA功能进行直接的遗传分析是可行的。我们的目标是三重：1）我们将使用遗传和化学遗传学方法来检验以下假设：RA信号传导模式在内耳中上皮投影，并且是形成了耳胶囊所必需的； 2）在微阵列分析中，我们确定了由RA信号传导向上和下调的候选靶基因；我们将表征它们的表达谱和内耳中的RA敏感性，并将通过基因敲低检查它们的功能。 3）为了推进可视化并剖析内耳形态发生的细胞动力学，我们将开发转基因斑马鱼线，这些斑马鱼线概括了RA介导的基因激活和体内内耳内RA合成的动力学。拟议的研究一起将揭示RA介导的基因活性控制的作用，并使我们能够将分子遗传相互作用与发展中耳朵的形态变化联系起来。