Journal
DIABETES
Volume 59, Issue 12, Pages 3090-3098Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db10-0624
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Funding
- National Institutes of Health (NIH) [DK63363]
- Juvenile Diabetes Research Foundation (JRDF) [1-2008-473]
- American Diabetes Association (ADA) [7-09-BS-41]
- University of Michigan Diabetes Research and Training Center Pilot & Feasibility (DRTC PF) [P60 DK020572]
- D.R.E.A.M. Foundation
- ADA
- University of Chicago [P60 DK20595]
- NIH [DK057768, DK074966, DK065131, DK071052, HD36720, T32DK07563, DK073716, DK69603, DK66636, DK072473]
- American Heart Association
- JRDF [1-2007-548, 1-2006-219, 1-2008-147, 1-2008-512]
- Vanderbilt DRTC PF [P60 DK020593]
- U.S. Department of Veterans Affairs Research Service
- National Institute of Diabetes and Digestive and Kidney Diseases DRTCs from the University of Chicago [P60 DK020595]
- University of Michigan [P60 DK020572]
- Vanderbilt University [P60 DK020593]
- Vanderbilt Mouse Metabolic Phenotyping Center [DK59637]
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OBJECTIVE-Conditional gene targeting has been extensively used for in vivo analysis of gene function in beta-cell biology. The objective of this study was to examine whether mouse transgenic Cre lines, used to mediate beta-cell- or pancreas-specific recombination, also drive Cre expression in the brain. RESEARCH DESIGN AND METHODS-Transgenic Cre lines driven by Ins1, Ins2, and Pdx1 promoters were bred to R26R reporter strains. Cre activity was assessed by P-galactosidase or yellow fluorescent protein expression in the pancreas and the brain. Endogenous Pdx1 gene expression was monitored using Pdx1(tm1Cvw) lacZ knock-in mice. Cre expression in beta-cells and co-localization of Cre activity with orexin-expressing and leptin-responsive neurons within the brain was assessed by immunohistochemistry. RESULTS-ll transgenic Cre lines examined that used the Ins2 promoter to drive Cre expression showed widespread Cre activity in the brain, whereas Cre lines that used Pdx1 promoter fragments showed more restricted Cre activity primarily within the hypothalamus. Immunohistochemical analysis of the hypothalamus from Tg(Pdx1-cre)(89.1Dam) mice revealed Cre activity in neurons expressing orexin and in neurons activated by leptin. Tg(Ins1-Cre/ERT)(1LPhi) mice were the only line that lacked Cre activity in the brain. CONCLUSIONS-re-mediated gene manipulation using transgenic lines that express Cre under the control of the Ins2 and Pdx1 promoters are likely to alter gene expression in nutrient-sensing neurons. Therefore, data arising from the use of these transgenic Cre lines must be interpreted carefully to assess whether the resultant phenotype is solely attributable to alterations in the islet beta-cells. Diabetes 59:3090-3098, 2010
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