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Metal-responsive transcription factor-1 (MTF-1) is essential for embryonic liver development and heavy metal detoxification in the adult liver

YING WANG, URSULA WIMMER, PETER LICHTLEN, DANIEL INDERBITZIN^*, BRUNO STIEGER^*, PETER J. MEIER^*, LUKAS HUNZIKER, THOMAS STALLMACH, RHEA FORRER, THOMAS RÜLICKE^||, OLEG GEORGIEV and WALTER SCHAFFNER¹

Institute of Molecular Biology
^* Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine
Institute of Experimental Immunology, Institut für Klinische Pathologie
Veterinärmedizinisches Labor
^|| Biologisches Zentrallabor, University of Zurich, Switzerland

¹Correspondence: Institute of Molecular Biology, Winterhurerstr. 190, Universität Zürich, 8057 Zürich, Switzerland. E-mail: walter.schaffner{at}molbio.unizh.ch

Metal-responsive transcription factor-1 (MTF-1) activates the transcription of metallothionein genes and other target genes in response to heavy metal load and other stresses such as hypoxia and oxidative stress. It also has an essential function during embryogenesis: targeted disruption of Mtf1 in the mouse results in lethal liver degeneration on day 14 of gestation. Here we studied Mtf1 knockout mice at embryonic and adult stages, the latter by means of conditional knockout. Hepatocytes from Mtf1 null mutant and wild-type embryos were taken into culture on day 12.5 of gestation. Both initially appeared normal, but mutant cells were lost within a few days. Furthermore, Mtf1 null hepatocytes were poorly, if at all, rescued by cocultivation with wild-type rat embryo hepatocytes, indicating a cell-autonomous defect. When the Mtf1 gene was excised by Cre recombinase after birth in liver and bone marrow and to a lesser extent in other organs, mice were viable under non-stress conditions but highly susceptible to cadmium toxicity, in support of a role of MTF-1 in coping with heavy metal stress. An additional MTF-1 function was revealed upon analysis of the hematopoietic system in conditional knockout mice where leukocytes, especially lymphocytes, were found to be severely underrepresented. Together, these findings point to a critical role of MTF-1 in embryonic liver formation, heavy metal toxicity, and hematopoiesis.—Wang, Y., Wimmer, U., Lichtlen, P., Inderbitzin, D., Stieger, B., Meier, P. J., Hunziker, L., Stallmach, T., Forrer, T., Rülicke, T., Georgiev, O., Schaffner, W. Metal-responsive transcription factor-1 (MTF-1) is essential for embryonic liver development and heavy metal detoxification in the adult liver.

Key Words: heavy metal stress • cadmium toxicity • hematopoiesis • conditional knockout

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