title: Metal-responsive transcription factor-1 (MTF-1) is essential for embryonic liver development and heavy metal detoxification in the adult liver.
abstract: 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.
authors.affiliation: Institute of Molecular Biology, University of Zurich, Switzerland.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Ursula
authors.initials: U
authors.lastname: Wimmer
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtlen
authors.forename: Daniel
authors.initials: D
authors.lastname: Inderbitzin
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meier
authors.forename: Lukas
authors.initials: L
authors.lastname: Hunziker
authors.forename: Thomas
authors.initials: T
authors.lastname: Stallmach
authors.forename: Rhea
authors.initials: R
authors.lastname: Forrer
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.forename: Oleg
authors.initials: O
authors.lastname: Georgiev
authors.forename: Walter
authors.initials: W
authors.lastname: Schaffner
mesh_terms: D000818:Animals; D002104:Cadmium / Q000493:pharmacokinetics / Q000633:toxicity; D018920:Coculture Techniques; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D018390:Gene Targeting; D006411:Hematopoiesis, Extramedullary / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism / Q000637:transplantation; D008658:Inactivation, Metabolic; D007970:Leukopenia / Q000235:genetics; D008099:Liver / Q000196:embryology / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D019216:Metals, Heavy / Q000493:pharmacokinetics* / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009928:Organ Specificity; D010641:Phenotype; D011828:Radiation Chimera; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013047:Specific Pathogen-Free Organisms; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015032:Zinc / Q000493:pharmacokinetics / Q000633:toxicity; D000097809:Transcription Factor MTF-1
chemical_list: D002104:Cadmium; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D019216:Metals, Heavy; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D015032:Zinc; D000097809:Transcription Factor MTF-1