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

Recently, genome-wide association studies (GWAS) have linked the human LIN28B locus to height and timing of menarche [1-5]. LIN28B and its homolog LIN28 (hereafter, LIN28A) are functionally redundant RNA-binding proteins that block let-7 microRNA (miRNA) biogenesis [6-9]. lin-28 and let-7 were disco...

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Detalles Bibliográficos
Autores principales: Zhu, Hao, Shah, Samar, Shyh-Chang, Ng, Shinoda, Gen, Einhorn, William S., Viswanathan, Srinivas R., Takeuchi, Ayumu, Grasemann, Corinna, Rinn, John L., Lopez, Mary F., Hirschhorn, Joel N., Palmert, Mark R., Daley, George Q.
Formato: Texto
Lenguaje:English
Publicado: 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069638/
https://www.ncbi.nlm.nih.gov/pubmed/20512147
http://dx.doi.org/10.1038/ng.593
Descripción
Sumario:Recently, genome-wide association studies (GWAS) have linked the human LIN28B locus to height and timing of menarche [1-5]. LIN28B and its homolog LIN28 (hereafter, LIN28A) are functionally redundant RNA-binding proteins that block let-7 microRNA (miRNA) biogenesis [6-9]. lin-28 and let-7 were discovered in C. elegans as heterochronic regulators of larval and vulval development, but recently have been implicated in cancer, stem cell aging, and pluripotency [10-13]. The let-7 targets Myc, Kras, Igf2bp1 and Hmga2 are known regulators of mammalian body size and metabolism [14-18]. To explore the Lin28/let-7 pathway in vivo, we engineered transgenic mice to express Lin28a and observed increased body size, crown-rump length, and a delayed onset of puberty. While investigating metabolic and endocrine mechanisms of overgrowth, we observed increased glucose metabolism and insulin sensitivity in these transgenic mice. We report a mouse that models the human phenotypes associated with genetic variation in the Lin28/let-7 pathway.