Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies.
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.
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.
Hao
H
Zhu
Samar
S
Shah
Ng
N
Shyh-Chang
Gen
G
Shinoda
William S
WS
Einhorn
Srinivas R
SR
Viswanathan
Ayumu
A
Takeuchi
Corinna
C
Grasemann
John L
JL
Rinn
Mary F
MF
Lopez
Joel N
JN
Hirschhorn
Mark R
MR
Palmert
George Q
GQ
Daley
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D049628:Body Size / Q000235:genetics / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D023421:Models, Animal; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012741:Sexual Maturation / Q000235:genetics / Q000502:physiology*; D013997:Time Factors
D001786:Blood Glucose; D007328:Insulin; C488352:Lin-28 protein, mouse; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C542687:mirnlet7 microRNA, mouse; D005947:Glucose