The Role of MicroRNAs in Vertebrate Development

描述（由申请人提供）：microRNAs （miRNAs）编码约22nt小rna，调节其靶mrna的死基化，翻译和衰变。mirna有可能调节超过30%的人类基因，从人类发育到包括神经精神疾病和癌症在内的人类疾病，mirna在生物学的各个方面都发挥着重要作用。我们研究的长期目标是了解mirna如何调节基因表达以协调早期胚胎发生，以斑马鱼为模型系统。特别地，本研究以斑马鱼为模型系统，研究了microRNAs如何调节有效的信号分子来控制细胞在两种不同情况下的迁移：侧线迁移和血管生成。我们使用单个microRNA敲除和microRNA加工途径中的突变进行的初步研究表明，破坏miR-1和miR-430功能会导致i)侧线原基（脊椎动物中基质迁移的模型）的异常迁移和ii)血管生成过程中（在节段间血管，ISV）的迁移增加。该建议结合胚胎学操作和实时成像，以了解miR-1如何调节血管生成过程中的内皮细胞迁移，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过程中保持分离，以避免错误靶向迁移。总之，拟议的实验具有了解i) miRNA如何调节单个miRNA靶点以协调细胞迁移和血管生成过程中的胚胎发育，ii)它们如何调节有效信号分子的表达以确保组织间适当的信号传导水平的长期目标。

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.