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Conditional gene targeting in mouse pancreatic ß-Cells: analysis of ectopic Cre transgene expression in the brain.

Diabetes | Dec 30, 2010

OBJECTIVE: Conditional gene targeting has been extensively used for in vivo analysis of gene function in β-cell biology. The objective of this study was to examine whether mouse transgenic Cre lines, used to mediate β-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 β-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 β-cells and co-localization of Cre activity with orexin-expressing and leptin-responsive neurons within the brain was assessed by immunohistochemistry. RESULTS: All 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: Cre-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 β-cells.

Pubmed ID: 20802254 RIS Download

Mesh terms: Animals | Brain | Crosses, Genetic | Estrogen Antagonists | Female | Galactosides | Gene Targeting | Genes, Reporter | Immunoglobulin G | Immunohistochemistry | Insulin | Insulin-Secreting Cells | Integrases | Leptin | Male | Mice | Mice, Transgenic | Reverse Transcriptase Polymerase Chain Reaction | Swine | Tamoxifen

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Associated grants

  • Agency: NIDDK NIH HHS, Id: DK057768
  • Agency: NIDDK NIH HHS, Id: DK074966
  • Agency: NIDDK NIH HHS, Id: R01 DK071052
  • Agency: NIDDK NIH HHS, Id: P60 DK020593
  • Agency: NIDDK NIH HHS, Id: DK073716
  • Agency: NIDDK NIH HHS, Id: DK072473
  • Agency: NIDDK NIH HHS, Id: R01 DK057768
  • Agency: NIDDK NIH HHS, Id: DK69603
  • Agency: NICHD NIH HHS, Id: HD36720
  • Agency: NICHD NIH HHS, Id: R01 HD036720
  • Agency: NIDDK NIH HHS, Id: R01 DK074966
  • Agency: NIDDK NIH HHS, Id: P60 DK20595
  • Agency: NIDDK NIH HHS, Id: DK071052
  • Agency: NIDDK NIH HHS, Id: R01 DK063363
  • Agency: NIDDK NIH HHS, Id: R01 DK065131
  • Agency: NIDDK NIH HHS, Id: U01 DK072473
  • Agency: NIDDK NIH HHS, Id: DK66636
  • Agency: NIDDK NIH HHS, Id: P60 DK020572
  • Agency: NIDDK NIH HHS, Id: U01 DK089572
  • Agency: NIDDK NIH HHS, Id: DK63363
  • Agency: NIDDK NIH HHS, Id: R33 DK066636
  • Agency: BLRD VA, Id: I01 BX000666
  • Agency: NIDDK NIH HHS, Id: DK59637
  • Agency: NIDDK NIH HHS, Id: P30 DK020593
  • Agency: NIDDK NIH HHS, Id: T32DK07563
  • Agency: NIDDK NIH HHS, Id: R01 DK084236
  • Agency: NIDDK NIH HHS, Id: R01 DK073716
  • Agency: NIDDK NIH HHS, Id: DK065131
  • Agency: NIDDK NIH HHS, Id: R01 DK069603
  • Agency: NIDDK NIH HHS, Id: R56 DK071052
  • Agency: NIDDK NIH HHS, Id: R01 DK068764
  • Agency: NIDDK NIH HHS, Id: T32 DK007563
  • Agency: NIDDK NIH HHS, Id: R21 DK066636
  • Agency: NIDDK NIH HHS, Id: P60 DK020595
  • Agency: NIDDK NIH HHS, Id: U24 DK059637

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Allen Institute for Brain Science

Independent 501(c)(3) nonprofit medical research organization dedicated to accelerating the understanding of how the human brain works. Utilizing the mouse model system, a multidisciplinary group of neuroscientists, molecular biologists, informaticists, engineers, mathematicians, statisticians, and computational biologists have joined together to investigate expression of 20,000 genes in the adult mouse brain and to map gene expression to a cellular level beyond neuroanatomic boundaries. The data generated from this joint effort is contained in the publicly available Allen Brain Atlas application. Molecular approaches to understanding the functional organization of the brain promise new insights into the relationships between genes, brain, behavior and disease. To facilitate such insights, the Allen Institute produces large-scale projects and makes the resulting data and tools freely available online to scientists worldwide. These open resources, all available at www.brain-map.org, are intended to foster scientific discovery and collaboration. Atlases: Allen Developing Mouse Brain Atlas: A map of gene expression in the developing mouse brain. Building on the Allen Mouse Brain Atlas, this atlas reveals gene expression patterns from embryonic through postnatal stages to provide information about both spatial and temporal regulation of gene expression. Allen Spinal Cord Atlas: A genome-wide map of gene expression throughout the adult and juvenile mouse spinal cord. The Atlas was made possible through the generous support of a diverse consortium of funders, representing disease organizations, foundations, and corporate and private donors. Allen Mouse Brain Atlas (formerly Allen Brain Atlas): A genome-wide, three-dimensional map of gene expression in the adult mouse brain. Similar in scale to the Human Genome Project, the Atlas reveals the expression patterns of approximately 20,000 genes throughout the entire adult mouse brain down to the cellular level. The Allen Institutes inaugural project, the Atlas was completed in 2006. Studies: Mouse Diversity Study: Characterization of gene expression in the brain across genetic backgrounds and sex. Expanding on the Allen Mouse Brain Atlas, this resource includes data for 49 pharmaceutical drug target genes and a selected set of additional genes across seven mouse strains and in female mice. Transgenic Mouse Study: Comprehensive characterization of the expression patterns of genetically-controlled markers or tool genes in the brains of transgenic mice. Providing standardized, detailed, anatomical profiling of transgene expression throughout the brain, this dataset is intended to reveal the potential of each transgenic mouse line and help researchers choose the appropriate tools for their studies. Human Cortex Study: A collection of gene expression data in the adult human neocortex. Providing data for several categories of genes across different cortical regions and human individuals, including control and schizophrenic cases, the dataset has the potential to enable exploration of variability in cortical gene expression across different ages, between genders across different regions of the cortex and in schizophrenia. Sleep Study: A comprehensive collection of gene expression data in the mouse brain for five different conditions of sleep and wakefulness. Generated in collaboration with SRI International, this unique dataset is intended to help sleep researchers advance understanding of sleep deprivation and the dynamic changes underlying sleep/wake cycles. The sleep study was funded by an award from the U.S. Department of Defense.

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National Mouse Metabolic Phenotyping Centers

The mission is to advance medical and biological research by providing the scientific community with standardized, high quality metabolic and physiologic phenotyping services for mouse models of diabetes, diabetic complications, obesity and related disorders.

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