Lin28a (lin-28 homolog A (C. elegans)) and Lin28b (lin-28 homolog B (C. elegans)) encode RNA-binding proteins that block the biogenesis of Mirlet7 (let-7) microRNAs. Let-7 targets are known regulators of mammalian body size and metabolism.
This strain was constructed to determine whether altered let-7 expression might produce phenotypes opposite those of strains over-expressing Lin28a (see Stock No. 023910) or Lin28b (see Stock No. 0023911). It expresses Let-7S21L (let-7g Stem, mir-21 Loop) under the regulatory control of a Col1a1 (collagen, type I, alpha 1)-driven tetO promoter. Let-7S21L represents a chimeric Mirlet7g (microRNA let7g) stem/Mir21 (microRNA 21) loop fusion that cannot bind LIN28, thus allowing for let-7 processing despite Lin28 expression. This ensures that endogenous LIN28 cannot block pri- or pre-let-7g biosynthesis.
Mirlet7g/Mir21 expression can be regulated in progeny derived from crosses with rtTA or tTA mice. When crossed with Gt(ROSA)26Sor M2-rtTA strain (see Stock No. 006965), uninduced male mice exhibit no leakiness of expression and exhibit no growth or glucose phenotypes. Widespread induction from three weeks of age onward increases mature MIRLET7G levels in liver (>50-fold), skin (>20-fold), fat (approximately 4-fold) and muscle (approximately 4-fold). Induced animals show reduced body size and growth rates. After 5 days of induction, mice produce an increase in fed state glucose. Glucose tolerance testing reveals glucose intolerance in mice fed either a normal or high fat diet. Insulin tolerance testing fails to detect a difference in insulin sensitivity. Mutant mice produce more insulin than control mice.
