ERYTHROID MATURATION AND GLOBIN GENE-EXPRESSION IN MICE WITH COMBINEDDEFICIENCY OF NF-E2 AND NRF-2

NF-E2 binding sites, located in distant regulatory sequences, may be i mportant for high level alpha- and beta-globin gene expression. Surpri singly, targeted disruption of each subunit of NF-E2 has either little or no effect on erythroid maturation in mice. For p18 NF-E2, this lac k of effect is due, at least in part, to the presence of redundant pro teins. For p45 NF-E2, one possibility is that NF-E2-related factors, N rf-1 or Nrf-2, activate globin gene expression in the absence of NF-E2 , To test this hypothesis for Nrf-2, we disrupted the Nrf-2 gene by ho mologous recombination. Nrf-2-deficient mice had no detectable hematop oietic defect. In addition, no evidence was found for reciprocal upreg ulation of NF-E2 or Nrf-2 protein in fetal liver cells deficient for e ither factor. Fetal liver cells deficient for both NF-E2 and Nrf-5 exp ressed normal levels of alpha- and beta-globin, Mature mice with combi ned deficiency of NF-E2 and Nrf-2 did not exhibit a defect in erythroi d maturation beyond that seen with loss of NF-E2 alone. Thus, the pres ence of a mild erythroid defect in NF-E2-deficient mice is not the res ult of compensation by Nrf-2. (C) 1998 by The American Society of Hema tology.