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Nat Genet. 2010 Jul;42(7):626-30. doi: 10.1038/ng.593. Epub 2010 May 30.

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

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1
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.

Abstract

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.

PMID:
20512147
PMCID:
PMC3069638
DOI:
10.1038/ng.593
[Indexed for MEDLINE]
Free PMC Article
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