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

Howard Hughes Medical Institute, Boston, Massachusetts, USA.
Nature Genetics (Impact Factor: 29.35). 07/2010; 42(7):626-30. DOI: 10.1038/ng.593
Source: PubMed


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.

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Available from: Corinna Grasemann
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    • "This role for Mkrn+LIN-28 may be contextdependent , as there are instances where LIN-28 promotes differentiation and where Mkrn is Development @BULLET Advance article associated with undifferentiated states (Cassar et al., 2015, O'Malley et al., 2013, Polesskaya et al., 2007, Walker et al., 2007). Also like LIN-28, Mkrn3 is involved in timing the onset of the human J/A transition (Abreu et al., 2013, Gajdos et al., 2010, Ong et al., 2009, Perry et al., 2009, Zhu et al., 2010). Specifically, alleles expected to reduce or abolish Mkrn3 function were implicated as causal factors of precocious pubertal onset as early as 5 years of age (Abreu et al., 2013). "
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    • "Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. findings are not contradictory to the more general concept of antagonistic pleiotropy (Williams, 1957) according to which, specific factors may have beneficial and detrimental effects depending on the period of time. However, delayed reproductive development may also correlate with somatic overgrowth in mice overexpressing LIN28B (Zhu et al., 2010), pointing to the fact that the connections between growth and reproductive development may not be unidirectional. Both somatic growth and reproductive development do represent early events in individual ontogeny. "
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    • "In total, $40% of the OSKM-iPSC lines gave rise to live pups, compared to 80% of the SNEL-iPSC lines. In general, the adult ''all-SNEL-iPSC'' mice were healthy and fertile (Figures 2B and S2C), although some mice exhibited some phenotypes that are purely related to leaky expression of Lin28, such as long tail and ears and flattened nose as described in (Zhu et al., 2010, 2011), and several individuals died prematurely after 1 year. To exploit the maximum potential of the cells and determine whether the developmental differences between these two types of iPSCs would be further exacerbated, we cultured the 20 iPSC lines in 2i medium (LIF, GSK3b, and Mek 1/2 inhibitors "
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