The Role of MicroRNAs in Vertebrate Development

描述(申请人提供)：microRNAs(MiRNAs)编码~22nt的小RNA，调节其目标mRNAs的去烯基化、翻译和衰变。MiRNAs有可能调控超过30%的人类基因，在生物学的各个方面发挥着重要作用，从人类发育到包括神经精神障碍和癌症在内的人类疾病。我们研究的长期目标是以斑马鱼为模型系统，了解miRNAs如何调控基因表达来协调早期胚胎发育。特别是，这项建议侧重于microRNAs如何在发育过程中的两个不同环境中调节强大的信号分子来控制细胞迁移：侧线迁移和以斑马鱼为模型系统的血管生成。我们的初步研究使用了单个microRNA下调和突变的microRNA加工途径表明，miR-1和miR-430功能的中断导致：1)侧线原基的异常迁移(脊椎动物的胎盘迁移模型)；2)血管生成过程中(节间血管，ISV)迁移增加。该建议结合胚胎学操作和实时成像，以了解miR-1如何在血管生成目标1中调控内皮细胞迁移，并了解miR-430如何确保由趋化因子信号sdf1a驱动的不同迁移路径在发育期间保持分离，以避免错误靶向迁移目标2。总之，拟议的实验有一个长期目标，即了解i)miRNA如何调控单个miRNA靶标，以协调细胞迁移和血管生成过程中的胚胎发育，ii)它们如何调节强大的信号分子的表达，以确保组织之间适当的信号水平。

DESCRIPTION (provided by applicant): microRNAs (miRNAs) encode ~22nt small RNAs that regulate deadenylation, translation, and decay of their target mRNAs. With the potential to regulate more that 30% of the human genes, miRNAs play fundamental roles in every aspect of biology from human development, to human disease including neuropsychiatric disorders and cancer. The long-term goal of our research is to understand how miRNAs regulate gene expression to orchestrate early embryogenesis, using zebrafish as a model system. In particular, this proposal focuses on how microRNAs regulate potent signaling molecules to control cell migration in two different contexts during development: lateral line migration and angiogenesis using zebrafish as a model system. Our preliminary studies have used single microRNA knock down and mutants in the microRNA processing pathway indicate that disrupting miR-1 and miR-430 function causes i) abnormal migration of the lateral line primordium (a model for placode migration in vertebrates) and ii) increased migration during angiogenesis (in the intersegmental vessels, ISV). This proposal combines embryological manipulations and live imaging, to understand how miR-1 regulate endothelial cell migration during angiogenesis Aim 1 and understand how miR-430 ensures that different migratory paths driven by the chemokine signaling sdf1a remain separated during development to avoid mis-targeted migration Aim 2. In summary, the proposed experiments have the long term goal of understanding i) how miRNAs regulate individual miRNA targets to orchestrate embryonic development during cell migration, and angiogenesis, ii) how they modulate the expression of potent signaling molecules to ensure the appropriate level of signaling between tissues.