The transcription factors MTF-1 and USF1 cooperate to regulate mouse metallothionein-I expression in response to the essential metal zinc in visceral endoderm cells during early development

• Published in: The EMBO journal 2001-03, Vol.20 (5), p.1114-1122
• Main Authors: Andrews, Glen K., Lee, Dae Kee, Ravindra, Rudravajhala, Lichtlen, Peter, Sirito, Mario, Sawadogo, Michele, Schaffner, Walter
• Format: Article
• Language: English
• Subjects: Alkaline Phosphatase - genetics; Animals; Diet; DNA-Binding Proteins - metabolism; Embryonic and Fetal Development - drug effects; Embryonic and Fetal Development - genetics; Embryos; endoderm; Endoderm - cytology; Endoderm - drug effects; Endoderm - metabolism; Female; Gene Deletion; Gene Expression Regulation, Developmental - drug effects; Genotype; helix-loop-helix protein; Histocytochemistry; Metallothionein - genetics; Metallothionein - metabolism; metallothionein-I; Mice; Mice, Knockout; Mice, Transgenic; MT-I gene; MTF-1; MTF-1 protein; Pregnancy; Promoter Regions, Genetic - genetics; Response Elements - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transcription Factor MTF-1; Transcription Factors - genetics; Transcription Factors - metabolism; Upstream Stimulatory Factors; USF; USF1 protein; Yolk Sac - cytology; Yolk Sac - drug effects; Yolk Sac - embryology; Yolk Sac - metabolism; Zinc; Zinc - administration & dosage; Zinc - deficiency; Zinc - pharmacology
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/20.5.1114

During early development of the mouse embryo, expression of the metallothionein‐I ( MT‐I ) gene is heightened specifically in the endoderm cells of the visceral yolk sac. The mechanisms of regulation of this cell‐specific pattern of expression of metallothionein‐I are unknown. However, it has recently been shown that MTF‐1, functioning as a metalloregulatory transcription factor, activates metallothionein genes in response to the essential metal zinc. In contrast with the metallothionein genes, MTF‐1 is essential for development; null mutant embryos die due to liver degeneration. We report here that MTF‐1 is absolutely essential for upregulation of MT‐I gene expression in visceral endoderm cells and that optimal expression also involves interactions of the basic helix–loop–helix upstream stimulatory factor‐1 (USF1) with an E‐box1‐containing sequence at −223 bp in the MT‐I promoter. Expression of MT‐I in visceral endoderm cells was dependent on maternal dietary zinc. Thus, the essential metal, zinc, apparently provides the signaling ligand that activates cell‐ specific MT‐I expression in visceral endoderm cells.