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Transcription of the mouse alpha-fetoprotein (AFP) gene, which is expressed at high levels in the visceral endoderm of the yolk sac and fetal liver and at low levels in the fetal gut, is regulated by three distinct upstream enhancer regions. To investigate the activities of these regions, each enhancer was individually linked to a heterologous human beta-globin promoter fused to the mouse class I H-2Dd structural gene. When tested in transgenic mice, the beta-globin promoter alone has minimal activity. We find that all three enhancers activate the beta-globin promoter in an AFP-like pattern; i.e., activity is detected in the yolk sac, fetal liver, and fetal gut. The enhancers remain active in the livers and guts of adult mice, consistent with previous studies showing that postnatal AFP repression is due not to the loss of enhancer activity but to a dominant repressor region. Enhancer III also functions in the brain. In addition, these studies reveal that the three enhancers exhibit different position-dependent activities in the adult liver. Enhancers I and II are most active in hepatocytes surrounding the central vein, with a gradual decrease in activity along the hepatic plates toward the portal triad. Enhancer III is active exclusively in hepatocytes surrounding the central vein. These data represent the first examples of individual control elements exhibiting positionally regulated activity in adult liver.