Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Children's Hospital Boston and Dana Farber Cancer Institute, Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
Nat Genet. 2010 Jul;42(7):626-30. doi: 10.1038/ng.593. Epub 2010 May 30.
Recently, genome-wide association studies have implicated the human LIN28B locus in regulating height and the timing of menarche. LIN28B and its homolog LIN28A are functionally redundant RNA-binding proteins that block biogenesis of let-7 microRNAs. lin-28 and let-7 were discovered in Caenorhabditis elegans as heterochronic regulators of larval and vulval development but have recently been implicated in cancer, stem cell aging and pluripotency. The let-7 targets Myc, Kras, Igf2bp1 and Hmga2 are known regulators of mammalian body size and metabolism. To explore the function of the Lin28-Let-7 pathway in vivo, we engineered transgenic mice to express Lin28a and observed in them increased body size, crown-rump length and delayed onset of puberty. Investigation of metabolic and endocrine mechanisms of overgrowth in these transgenic mice revealed increased glucose metabolism and insulin sensitivity. Here we report a mouse that models the human phenotypes associated with genetic variation in the Lin28-Let-7 pathway.
最近，全基因组关联研究表明人类 LIN28B 基因座在调节身高和初潮时间方面发挥作用。LIN28B 和其同源物 LIN28A 是功能冗余的 RNA 结合蛋白，可阻止 let-7 微 RNA 的生物发生。lin-28 和 let-7 最初是在秀丽隐杆线虫中发现的，它们是幼虫和生殖腺发育的异时调控因子，但最近与癌症、干细胞衰老和多能性有关。let-7 的靶标 Myc、Kras、Igf2bp1 和 Hmga2 是已知的哺乳动物体型和代谢的调节因子。为了探索 Lin28-Let-7 通路在体内的功能，我们构建了表达 Lin28a 的转基因小鼠，并观察到它们的体型增加、头臀长增加和青春期开始延迟。对这些转基因小鼠过度生长的代谢和内分泌机制的研究表明，葡萄糖代谢和胰岛素敏感性增加。本文报道了一种模拟人类 LIN28-Let-7 通路遗传变异相关表型的小鼠模型。
