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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Body Size / genetics
  • Body Size / physiology*
  • Female
  • Gene Expression Profiling
  • Genetic Association Studies*
  • Glucose / metabolism
  • Humans
  • Insulin / blood
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Models, Animal
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sexual Maturation / genetics
  • Sexual Maturation / physiology*
  • Time Factors

Substances

  • Blood Glucose
  • Insulin
  • Lin-28 protein, mouse
  • MicroRNAs
  • RNA-Binding Proteins
  • mirnlet7 microRNA, mouse
  • Glucose

Associated data

  • GEO/GSE21226