Mice with DNA repair gene Ercc1 deficiency in a neural crest lineage are a model for late-onset Hirschsprung disease |
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| Authors: | Jim Selfridge Liang Song David G Brownstein David W Melton |
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| Institution: | 1. Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Mayfield Road, Edinburgh EH9 3JR, UK;2. Institute of Genetics and Molecular Medicine, University of Edinburgh, MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK;3. Research Animal Pathology Core Laboratory, Queen''s Medical Research Institute, 47 Little France Crescent, University of Edinburgh, Edinburgh EH16 4TJ, UK;1. Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland;2. Translational Surgical Pathology, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland;3. Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland;4. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland;1. Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK;2. MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK;1. Department of Cell and Tissue Biology, Program in Craniofacial and Mesenchymal Biology and Institute for Human Genetics, University of California at San Francisco, San Francisco, CA 94143, United States;2. Department of Developmental and Regenerative Biology, Mt. Sinai School of Medicine, New York, NY 10029, United States;1. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX;2. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX;3. Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX |
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| Abstract: | The Ercc1 gene is essential for nucleotide excision repair and is also important in recombination repair and the repair of interstrand crosslinks. We have previously used a floxed Ercc1 allele with a keratinocyte-specific Cre recombinase transgene to inactivate Ercc1 in the epidermal layer of the skin and so generate a mouse model for UV-induced non-melanoma skin cancer. Now, in an attempt to generate a model for UV-induced melanoma, we have used the floxed Ercc1 allele in combination with a Cre transgene under the control of the tyrosinase gene promoter to produce mice with Ercc1-deficient melanocytes that are hypersensitive to UV irradiation. These animals developed normally, but died when 4–6 months old with severe colonic obstruction. Melanocytes are derived from the neural crest and the tyrosinase promoter is also expressed in additional neural crest-derived lineages, including the progenitors of the parasympathetic nervous system that innervates the gastrointestinal tract and controls gut peristalsis. A functional enteric nervous system developed in floxed Ercc1 mice with the tyrosinase Cre transgene, but was found to have degenerated in the colons of affected mice. We suggest that accumulating unrepaired endogenous DNA damage in the Ercc1-deficient colonic parasympathetic ganglia leads to the degeneration of this network and results in a colonic obstructive disorder that resembles late-onset Hirschsprung disease in man. |
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