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Sci Rep. 2016 Sep 2;6:32453. doi: 10.1038/srep32453.

Identification of mutations through dominant screening for obesity using C57BL/6 substrains.

Author information

1
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
2
Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, 1-1-1 Tennodai, Tsukuba Ibaraki, 305-8575, Japan.
3
Technology and Development Team for Mouse Phenotype Analysis, RIKEN BioResource Center, Tsukuba, Ibaraki 305-0074, Japan.
4
Department of Neuroscience, University of Texas Southwestern Medical Center at Dallas, Texas 75390, USA.
5
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
6
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Taxas, 75390, USA.
7
Department of Anatomy, Toho University Faculty of Medicine, Tokyo 143-8540, Japan.
8
Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Texas 75390, USA.

Abstract

The discovery of leptin substantiated the usefulness of a forward genetic approach in elucidating the molecular network regulating energy metabolism. However, no successful dominant screening for obesity has been reported, which may be due to the influence of quantitative trait loci between the screening and counter strains and the low fertility of obese mice. Here, we performed a dominant screening for obesity using C57BL/6 substrains, C57BL/6J and C57BL/6N, with the routine use of in vitro fertilization. The screening of more than 5000 mutagenized mice established two obese pedigrees in which single nucleotide substitutions in Mc4r and Sim1 genes were identified through whole-exome sequencing. The mutation in the Mc4r gene produces a premature stop codon, and the mutant SIM1 protein lacks transcriptional activity, showing that the haploinsufficiency of SIM1 and MC4R results in obesity. We further examined the hypothalamic neuropeptide expressions in the mutant pedigrees and mice with diet-induced obesity, which showed that each obesity mouse model has distinct neuropeptide expression profiles. This forward genetic screening scheme is useful and applicable to any research field in which mouse models work.

PMID:
27585985
PMCID:
PMC5009433
DOI:
10.1038/srep32453
[Indexed for MEDLINE]
Free PMC Article

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