EMBRYONIC LETHALITY AND LIVER DEGENERATION IN MICE LACKING THE METAL-RESPONSIVE TRANSCRIPTIONAL ACTIVATOR MTF-1

We have shown previously that the heavy metal-responsive transcription al activator MTF-1 regulates the basal and heavy metal-induced express ion of metallothioneins, To investigate the physiological function of MTF-1, we generated null mutant mice by targeted gene disruption. Embr yos lacking MTF-1 die in utero at approximately day 14 of gestation. T hey show impaired development of hepatocytes and, at later stages, liv er decay and generalized edema. MTF-1(-/-) embryos fail to transcribe metallothionein I and II genes, and also show diminished transcripts o f the gene which encodes the heavy-chain subunit of the gamma-glutamyl cysteine synthetase, a key enzyme for glutathione biosynthesis. Metall othionein and glutathione are involved in heavy metal homeostasis and detoxification processes, such as scavenging reactive oxygen intermedi ates. Accordingly, primary mouse embryo fibroblasts lacking MTF-1 show increased susceptibility to the cytotoxic effects of cadmium or hydro gen peroxide, Thus, MTF-1 may help to control metal homeostasis and pr obably cellular redox state, especially during liver development. We a lso note that the MTF-1 null mutant phenotype hears some similarity to those of two other regulators of cellular stress response, namely c-J un and NF-kappa B (p65/RelA).