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PMID: 20512147 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature genetics ·Vol. 42 ·No. 7 ·2010-07-00 ·Pages 626-30

Zhu H, Shah S, Shyh-Chang N, Shinoda G, Einhorn WS, Viswanathan SR, Takeuchi A, Grasemann C, Rinn JL, Lopez MF, Hirschhorn JN, Palmert MR, Daley GQ

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.

MeSH Terms
Animals Blood Glucose/metabolism Body Size/genetics,physiology Female Gene Expression Profiling Genetic Association Studies Glucose/metabolism Humans Insulin/blood Male Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Transgenic MicroRNAs/genetics,metabolism Models, Animal Oligonucleotide Array Sequence Analysis Phenotype RNA-Binding Proteins/genetics,metabolism Reverse Transcriptase Polymerase Chain Reaction Sexual Maturation/genetics,physiology Time Factors
Chemicals
Blood Glucose Insulin Lin-28 protein, mouse MicroRNAs RNA-Binding Proteins mirnlet7 microRNA, mouse Glucose
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Zhu Hao
Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Children's Hospital Boston and Dana Farber Cancer Institute, Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
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
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.593
Published
2010-07-00
Epub
2010-00-30
Pages
626-30
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC3069638
Subset
IM
Grants
NCI NIH HHS · K08 CA157727 · United States
Howard Hughes Medical Institute · United States
NIH HHS · DP1 OD000256 · United States
NCI NIH HHS · T32 CA009172 · United States
NIH HHS · DP1 OD000256-05 · United States
NCI NIH HHS · 5 T32 CA09172-35 · United States
NICHD NIH HHS · R01HD048960 · United States
Databases
GEO
GSE21226
External Links
PubMed source DOI: 10.1038/ng.593 PMC Full Text View journal details
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