Targeted insertion of two Mthfr promoters in mice reveals temporal- and tissue-specific regulation.


Journal Article

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.

Full Text

Cited Authors

  • Pickell, L; Wu, Q; Wang, X-L; Leclerc, D; Friedman, H; Peterson, AC; Rozen, R

Published Date

  • December 2011

Published In

Volume / Issue

  • 22 / 11-12

Start / End Page

  • 635 - 647

PubMed ID

  • 21769670

Pubmed Central ID

  • 21769670

Electronic International Standard Serial Number (EISSN)

  • 1432-1777

International Standard Serial Number (ISSN)

  • 0938-8990

Digital Object Identifier (DOI)

  • 10.1007/s00335-011-9351-5


  • eng