Lin28a Transgenic Mice Manifest Size and Puberty Phenotypes Identified in Human Genetic Association Studies

Overview

Journal Nat Genet

Specialty Genetics

Date 2010 Jun 1

PMID 20512147

Citations 174

Authors

Hao Zhu

Samar Shah

Ng Shyh-Chang

Gen Shinoda

William S Einhorn

Srinivas R Viswanathan

Ayumu Takeuchi

Corinna Grasemann

John L Rinn

Mary F Lopez

Joel N Hirschhorn

Mark R Palmert

George Q Daley

Affiliations

Soon will be listed here.

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.

Citing Articles

Shared Pathophysiological Mechanisms and Genetic Factors in Early Menarche and Polycystic Ovary Syndrome.

Tinano F, Machado I, Latronico A, Gomes L J Neurosci. 2025; 45(11).

PMID: 40074331 PMC: 11905354. DOI: 10.1523/JNEUROSCI.1681-24.2024.

Modulates mRNA Expression of Through Multiple Signaling Pathways Related to Glycolysis in GT1-7 Cells.

Xie Y, Li X, Wang M, Chu M, Cao G Animals (Basel). 2025; 15(2).

PMID: 39858120 PMC: 11758636. DOI: 10.3390/ani15020120.

Metabolic regulation in adult and aging skeletal muscle stem cells.

Sartorelli V, Ciuffoli V Genes Dev. 2024; 39(3-4):186-208.

PMID: 39662967 PMC: 11789647. DOI: 10.1101/gad.352277.124.

RNA Binding Proteins as Potential Therapeutic Targets in Colorectal Cancer.

Singh V, Singh A, Liu A, Fuchs S, Sharma A, Spiegelman V Cancers (Basel). 2024; 16(20).

PMID: 39456596 PMC: 11506615. DOI: 10.3390/cancers16203502.

Primary ovarian insufficiency: update on clinical and genetic findings.

Federici S, Rossetti R, Moleri S, Munari E, Frixou M, Bonomi M Front Endocrinol (Lausanne). 2024; 15:1464803.

PMID: 39391877 PMC: 11466302. DOI: 10.3389/fendo.2024.1464803.

References

Viswanathan S, Powers J, Einhorn W, Hoshida Y, Ng T, Toffanin S . Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet. 2009; 41(7):843-8. PMC: 2757943. DOI: 10.1038/ng.392. View

Polesskaya A, Cuvellier S, Naguibneva I, Duquet A, Moss E, Harel-Bellan A . Lin-28 binds IGF-2 mRNA and participates in skeletal myogenesis by increasing translation efficiency. Genes Dev. 2007; 21(9):1125-38. PMC: 1855237. DOI: 10.1101/gad.415007. View

Chang T, Zeitels L, Hwang H, Chivukula R, Wentzel E, Dews M . Lin-28B transactivation is necessary for Myc-mediated let-7 repression and proliferation. Proc Natl Acad Sci U S A. 2009; 106(9):3384-9. PMC: 2651245. DOI: 10.1073/pnas.0808300106. View

Clower C, Chatterjee D, Wang Z, Cantley L, Vander Heiden M, Krainer A . The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proc Natl Acad Sci U S A. 2010; 107(5):1894-9. PMC: 2838216. DOI: 10.1073/pnas.0914845107. View

Christiansen J, Kolte A, Hansen T, Nielsen F . IGF2 mRNA-binding protein 2: biological function and putative role in type 2 diabetes. J Mol Endocrinol. 2009; 43(5):187-95. DOI: 10.1677/JME-09-0016. View

Perry J, Stolk L, Franceschini N, Lunetta K, Zhai G, McArdle P . Meta-analysis of genome-wide association data identifies two loci influencing age at menarche. Nat Genet. 2009; 41(6):648-50. PMC: 2942986. DOI: 10.1038/ng.386. View

Weedon M, Lettre G, Freathy R, Lindgren C, Voight B, Perry J . A common variant of HMGA2 is associated with adult and childhood height in the general population. Nat Genet. 2007; 39(10):1245-50. PMC: 3086278. DOI: 10.1038/ng2121. View

Newman M, Thomson J, Hammond S . Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing. RNA. 2008; 14(8):1539-49. PMC: 2491462. DOI: 10.1261/rna.1155108. View

Krewson T, Supelak P, Hill A, Singer J, Lander E, Nadeau J . Chromosomes 6 and 13 harbor genes that regulate pubertal timing in mouse chromosome substitution strains. Endocrinology. 2004; 145(10):4447-51. DOI: 10.1210/en.2004-0543. View

10.

Sulem P, Gudbjartsson D, Rafnar T, Holm H, Olafsdottir E, Olafsdottir G . Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche. Nat Genet. 2009; 41(6):734-8. DOI: 10.1038/ng.383. View

11.

Nishino J, Kim I, Chada K, Morrison S . Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16Ink4a and p19Arf Expression. Cell. 2008; 135(2):227-39. PMC: 2582221. DOI: 10.1016/j.cell.2008.09.017. View

12.

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

13.

Yang D, Moss E . Temporally regulated expression of Lin-28 in diverse tissues of the developing mouse. Gene Expr Patterns. 2003; 3(6):719-26. DOI: 10.1016/s1567-133x(03)00140-6. View

14.

Berti L, Gammeltoft S . Leptin stimulates glucose uptake in C2C12 muscle cells by activation of ERK2. Mol Cell Endocrinol. 2000; 157(1-2):121-30. DOI: 10.1016/s0303-7207(99)00154-9. View

15.

Gao P, Tchernyshyov I, Chang T, Lee Y, Kita K, Ochi T . c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009; 458(7239):762-5. PMC: 2729443. DOI: 10.1038/nature07823. View

16.

Yu J, Vodyanik M, Smuga-Otto K, Antosiewicz-Bourget J, Frane J, Tian S . Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007; 318(5858):1917-20. DOI: 10.1126/science.1151526. View

17.

Viswanathan S, Daley G, Gregory R . Selective blockade of microRNA processing by Lin28. Science. 2008; 320(5872):97-100. PMC: 3368499. DOI: 10.1126/science.1154040. View

18.

Nathan B, Hodges C, Supelak P, Burrage L, Nadeau J, Palmert M . A quantitative trait locus on chromosome 6 regulates the onset of puberty in mice. Endocrinology. 2006; 147(11):5132-8. DOI: 10.1210/en.2006-0745. View

19.

Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C . let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell. 2007; 131(6):1109-23. DOI: 10.1016/j.cell.2007.10.054. View

20.

Christofk H, Vander Heiden M, Harris M, Ramanathan A, Gerszten R, Wei R . The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008; 452(7184):230-3. DOI: 10.1038/nature06734. View