Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies

Recently, genome-wide association studies (GWAS) have linked the human LIN28B locus to height and timing of menarche [1-5]. LIN28B and its homolog LIN28 (hereafter, LIN28A) are functionally redundant RNA-binding proteins that block let-7 microRNA (miRNA) biogenesis [6-9]. lin-28 and let-7 were discovered in C. elegans as heterochronic regulators of larval and vulval development, but recently have been implicated in cancer, stem cell aging, and pluripotency [10-13]. The let-7 targets Myc, Kras, Igf2bp1 and Hmga2 are known regulators of mammalian body size and metabolism [14-18]. To explore the Lin28/let-7 pathway in vivo, we engineered transgenic mice to express Lin28a and observed increased body size, crown-rump length, and a delayed onset of puberty. While investigating metabolic and endocrine mechanisms of overgrowth, we observed increased glucose metabolism and insulin sensitivity in these transgenic mice. We report a mouse that models the human phenotypes associated with genetic variation in the Lin28/let-7 pathway.