Targeted insertion of two Mthfr promoters in mice reveals temporal- and tissue-specific regulation
| Autor: | Hana Friedman, Alan C. Peterson, Rima Rozen, Daniel Leclerc, Qing Wu, Laura Pickell, Xiao-Ling Wang |
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| Rok vydání: | 2011 |
| Předmět: |
Genetically modified mouse
Central Nervous System Male Genotype Methylenetetrahydrofolate reductase deficiency Transgene Placenta Mice Transgenic Polymorphism Single Nucleotide Mice Pregnancy Testis Genetics medicine Animals Promoter Regions Genetic Methylenetetrahydrofolate Reductase (NADPH2) biology Myocardium Neural tube Neural crest Promoter Methylation medicine.disease Embryo Mammalian Molecular biology digestive system diseases Mice Inbred C57BL medicine.anatomical_structure Psychotic Disorders Muscle Spasticity Methylenetetrahydrofolate reductase biology.protein Blood Vessels Female Homocystinuria |
| Zdroj: | Mammalian genome : official journal of the International Mammalian Genome Society. 22(11-12) |
| ISSN: | 1432-1777 |
| Popis: | Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, synthesizes 5-methyltetrahydrofolate, the main circulatory form of folate which is required for maintaining nontoxic levels of homocysteine and providing one-carbon units for methylation. A common 677C → T variant in MTHFR confers mild MTHFR deficiency and has been associated with a number of human disorders, including neural tube defects and vascular disease. Two promoters of Mthfr, designated as upstream and downstream promoters, are located upstream of a transcription start site cluster and have previously demonstrated cell-specific activities. In this study we used a unique approach for targeted, single-copy transgene insertion to generate transgenic mice carrying a Mthfr upstream or Mthfr downstream promoter-reporter construct located 5′ to the endogenous Hprt (hypoxanthine-guanine phosphoribosyltransferase) locus. The Mthfr downstream promoter demonstrated activity in the neural tube, neural crest cells, dorsal root ganglia, heart, and endothelial cells of blood vessels in 10.5-days post coitum embryos and placentas. Upstream promoter activity was absent at this developmental stage. Postnatally, both promoters demonstrated activity in the brain stem, hippocampus, and thalamus of 1-week-old brain that became stronger in the adult. The Mthfr upstream promoter also showed activity in the cerebellum and cerebral cortex. Both promoters were active in male reproductive tissues, including 1-week-old epididymides, and there was upstream promoter-specific activity in the adult testis. Our investigation of Mthfr regulation in an in vivo mouse model revealed temporal- and tissue-specific regulation that supports important roles for MTHFR in the developing embryo, and in postnatal brain and male reproductive tissues. |
| Databáze: | OpenAIRE |
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