miR-200 miRNAs regulate motile ciliogenesis in respiratory epithelia

在呼吸道上皮中，杯状细胞分泌粘液以捕获外来颗粒并侵入 病原体;多纤毛细胞（MCC）提供运动纤毛的同步跳动， 从呼吸道挤出粘液MCCs与杯状细胞的协调功能 构成呼吸道感染防御机制的基础。单个MCC包含 数以百计的活动纤毛，协调地跳动，产生连续和定向的运动 细胞外液来清除肺组织。因此，MCC中的能动纤毛发生特别重要。 对呼吸道上皮细胞的肺防御很重要。虽然它已经变得越来越 很清楚，非编码RNA是发育分子网络的组成部分， 和疾病，大多数关于运动纤毛发生和MCC生物学的研究都集中在蛋白质- 编码基因使用小鼠模型，我们的初步研究鉴定了miR-200 miRNA， 在呼吸道上皮细胞中的重要作用。miR-200家族由五个高度同源的， 在呼吸系统中共同表现出高水平表达的进化上保守的miRNA， 上皮细胞，特别是多纤毛细胞。miR-200家族的冗余性， 哺乳动物基因组，结合它们在多纤毛细胞中的强表达模式，赋予 对能动纤毛发生的强大功能调节。所有miR-200 miRNAs缺陷的小鼠死亡 出生后，表现出强烈的呼吸功能障碍，过多的粘液积聚， 受损的能动纤毛发生。利用老鼠和青蛙的遗传学，细胞生物学和分子生物学 方法，我们建议仔细描述miR-200缺陷型MCC的表型， 小鼠和人类，特别关注运动性纤毛的发育。此外，我们建议 研究miR-200在运动过程中功能的分子机制， 纤毛发生综合起来，这些拟议的研究不仅会加深我们对 动纤毛发生的分子基础，而且还提供了重要的见解，发展 用于治疗呼吸系统疾病的新诊断标志物和治疗剂。

In respiratory epithelia, goblet cells secrete mucus to trap foreign particles and invading pathogens; multiciliated cells (MCCs) provide synchronized beating of motile cilia, driving the extruded mucus out of the respiratory tract. The coordinated functions of MCCs and goblet cells constitute the basis for defense mechanism against respiratory infections. A single MCC contains hundreds of motile cilia that beat coordinately to generate continuous and directional movement of extracellular fluid for pulmonary clearance. Hence the motile ciliogenesis in MCCs is particularly important for the pulmonary defense in respiratory epithelia. Although it has become increasingly clear that non-coding RNAs are integral components of the molecular network for development and disease, most studies on motile ciliogenesis and MCC bioology have focused on protein- coding genes. Using mouse models, our preliminary studies identified miR-200 miRNAs with an essential role in respiratory epithelia. The miR-200 family consists of five highly homologous and evolutionarily conserved miRNAs that collectively exhibit a high-level expression in respiratory epithelia, and particularly, in multiciliated cells. The redundancy of the miR-200 family in the mammalian genome, combined with their strong expression patterns in multiciliated cells, confer a robust functional regulation on motile ciliogenesis. Mice deficient for all miR-200 miRNAs die postnatally, exhibiting strong respiratory dysfunction, excessive mucus accumulation and impaired motile ciliogenesis. Using mouse and frog genetics, cell biology and molecular biology approaches, we proposed to carefully characterize the phenotype in miR-200 deficient MCCs in mouse and in human, with a particular focus on motile ciliagenesis. In addition, we propose to investigate the molecular mechanisms underlying the miR-200 functions during motile ciliogenesis. Taken together, these proposed studies will not only deepen our understanding on the molecular basis of motile ciliogenesis, but also provide important insights into the development of new diagnostic markers and therapeutical agents for treating respiratory conditions.