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

Nature Genetics volume 42, pages 626–630 (2010)Cite this article

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Abstract

Recently, genome-wide association studies have implicated the human LIN28B locus in regulating height and the timing of menarche1,2,3,4,5. LIN28B and its homolog LIN28A are functionally redundant RNA-binding proteins that block biogenesis of let-7 microRNAs6,7,8,9. 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 pluripotency10,11,12,13. The let-7 targets Myc, Kras, Igf2bp1 and Hmga2 are known regulators of mammalian body size and metabolism14,15,16,17,18. 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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Figure 1: Lin28a-inducible mice display increased growth and a proportional increase in organ sizes.
Figure 2: Lin28a transgenic mice show a delay in the onset of puberty.
Figure 3: Ectopic expression of Lin28a in transgenic mice.
Figure 4: Lin28a transgenic mice show increased glucose uptake and insulin sensitivity.

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Change history

  • 13 June 2010

    In the version of this article initially published online, the authors failed to acknowledge the source of the unpublished Lin28a knockout mouse strain. These mice were provided by Eric Moss at The University of Medicine and Dentistry of New Jersey and will be described in a separate report (S.R.V., G.S., H.Z., W.S.E., G.C. Heffner et al., unpublished data). The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

Lin28a knockout mice were generously provided by Eric Moss at The University of Medicine and Dentistry of New Jersey and will be described separately (S.R.V., G.S., H.Z., W.S.E., G.C. Heffner et al., unpublished data). We acknowledge J. Powers, H. Rajagopalan and M. Kharas for invaluable discussions and advice regarding this work. We also thank Y.-H. Loh, M. White, L. Wang and J. Majzoub for in-depth discussion and endocrine expertise. This work was supported by a Graduate Training in Cancer Research Grant (5 T32 CA09172-35) to H.Z., a NIH grant (R01HD048960) to M.R.P., a NIH Directors Pioneer Award and a HHMI grant to G.Q.D.

Author information

Authors and Affiliations

  1. Division of Pediatric Hematology/Oncology, Stem Cell Transplantation Program, Children's Hospital Boston and Dana Farber Cancer Institute, Boston, Massachusetts, USA

    Hao Zhu, Samar Shah, Ng Shyh-Chang, Gen Shinoda, William S Einhorn, Srinivas R Viswanathan, Ayumu Takeuchi & George Q Daley

  2. Harvard Stem Cell Institute, Boston, Massachusetts, USA

    Hao Zhu, Samar Shah, Ng Shyh-Chang, Gen Shinoda, William S Einhorn, Srinivas R Viswanathan, Ayumu Takeuchi & George Q Daley

  3. Division of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA

    Hao Zhu

  4. Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts, USA

    William S Einhorn & George Q Daley

  5. Division of Endocrinology, The Hospital for Sick Children, Toronto, Canada

    Corinna Grasemann & Mark R Palmert

  6. Department of Paediatrics, The University of Toronto, Toronto, Canada

    Corinna Grasemann & Mark R Palmert

  7. The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    John L Rinn & Joel N Hirschhorn

  8. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    John L Rinn

  9. Division of Endocrinology, Children's Hospital of Boston, Boston, Massachusetts, USA

    Mary F Lopez & Joel N Hirschhorn

  10. Division of Genetics, Program in Genomics, Children's Hospital of Boston, Boston, Massachusetts, USA

    Joel N Hirschhorn

  11. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA

    Joel N Hirschhorn

  12. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA

    George Q Daley

  13. Howard Hughes Medical Institute, Boston, Massachusetts, USA

    George Q Daley

  14. Manton Center for Orphan Disease Research, Boston, Massachusetts, USA

    George Q Daley

Authors
  1. Hao Zhu
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Contributions

H.Z. and G.Q.D. conceived the experiments and wrote the manuscript. H.Z. performed all experiments unless otherwise indicated. S.S. contributed to the work in Figures 1, 2 and 4 and Supplementary Figures 4 and 5. N.S.-C. performed the GSEA microarray analysis and created Figure 4j–l. G.S. generated the data in Supplementary Figure 1a,b. W.S.E. performed mouse husbandry, genotyping and experiments shown in Supplementary Figure 3d. S.R.V. made the Lin28a mouse ES cell line and mouse strain. A.T. performed the mouse chimera injections for the generation of all the transgenic strains. C.G. provided experimental assistance for puberty phenotyping and isolation and processing of endocrine organs. J.L.R., M.F.L., J.N.H. and M.R.P. contributed reagents, analyzed data and edited the manuscript.

Corresponding author

Correspondence to George Q Daley.

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The authors declare no competing financial interests.

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Zhu, H., Shah, S., Shyh-Chang, N. et al. Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies. Nat Genet 42, 626–630 (2010). https://doi.org/10.1038/ng.593

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