TARGETED DISRUPTION OF THE GENE ENCODING HEPATOCYTE NUCLEAR FACTOR 3-GAMMA RESULTS IN REDUCED TRANSCRIPTION OF HEPATOCYTE-SPECIFIC GENES

The winged helix transcription factor hepatocyte nuclear factor 3 gamm a (HNF3 gamma) is expressed in embryonic endoderm and its derivatives liver, pancreas, stomach, and intestine, as well as in testis and ovar y. We have generated mice carrying an Hnf3g-lacZ fusion which deletes most of the HNF3 gamma coding sequence as well as 5.5 Wb of 3' flankin g region. Mice homozygous for the mutation are fertile, develop normal ly, and show no morphological defects. The mild phenotype change of th e Hnf3g(-/-) mice can be explained in part by an upregulation of HNF3 alpha and HNF3 beta in the liver of the mutant animals. Analysis of st eady-state mRNA levels as well as transcription rates showed that leve ls of expression of several HNF3 target genes (phosphoenolpyruvate car boxykinase, transferrin, tyrosine aminotransferase) were reduced by 50 to 70%, indicating that HNF3 gamma is an important activator of these genes in vivo.