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

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.

脊椎动物内耳发育对视黄酸 (RA) 信号的变化敏感，但 RA 控制的形态发生过程及其分子靶点在很大程度上尚未被探索。哺乳动物在内耳中共表达三种视黄醛脱氢酶，而斑马鱼发育中的内耳和侧翼组织中分别只存在 Aldh1a3 和 Aldh1a2。因此，完成斑马鱼耳囊中 RA 功能的直接遗传分析是可行的。我们的目标有三个：1）我们将使用遗传和化学遗传方法来检验以下假设：RA 信号传导在内耳中的上皮投射模式，并且是耳囊形成所必需的； 2) 在微阵列分析中，我们已经确定了 RA 信号传导上调和下调的候选靶基因；我们将表征它们在内耳中的表达谱和 RA 敏感性，并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系，以重现 RA 介导的基因激活和体内内耳内 RA 合成的动力学。总之，拟议的研究将揭示 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育中的内耳的形态变化联系起来。