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

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

doi:10.1038/ng.593

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

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

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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.

Original language	English (US)
Pages (from-to)	626-630
Number of pages	5
Journal	Nature genetics
Volume	42
Issue number	7
DOIs	https://doi.org/10.1038/ng.593
State	Published - Jul 2010

ASJC Scopus subject areas

Genetics

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Zhu, H., Shah, S., Shyh-Chang, N., Shinoda, G., Einhorn, W. S., Viswanathan, S. R., Takeuchi, A., Grasemann, C., Rinn, J. L., Lopez, M. F., Hirschhorn, J. N., Palmert, M. R., & Daley, G. Q. (2010). Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies. Nature genetics, 42(7), 626-630. https://doi.org/10.1038/ng.593

@article{b05670ac074b48a98e3426593183d333,

title = "Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies",

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.",

author = "Hao Zhu and Samar Shah and Ng Shyh-Chang and Gen Shinoda and Einhorn, {William S.} and Viswanathan, {Srinivas R.} and Ayumu Takeuchi and Corinna Grasemann and Rinn, {John L.} and Lopez, {Mary F.} and Hirschhorn, {Joel N.} and Palmert, {Mark R.} and Daley, {George Q.}",

note = "Funding Information: 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.",

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doi = "10.1038/ng.593",

language = "English (US)",

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T1 - Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies

AU - Zhu, Hao

AU - Shah, Samar

AU - Shyh-Chang, Ng

AU - Shinoda, Gen

AU - Einhorn, William S.

AU - Viswanathan, Srinivas R.

AU - Takeuchi, Ayumu

AU - Grasemann, Corinna

AU - Rinn, John L.

AU - Lopez, Mary F.

AU - Hirschhorn, Joel N.

AU - Palmert, Mark R.

AU - Daley, George Q.

N1 - Funding Information: 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.

PY - 2010/7

Y1 - 2010/7

N2 - 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.

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

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