Developmental Action of Estrogen Receptor-α Feminizes the Growth Hormone-Stat5b Pathway and Expression ofCyp2a4andCyp2d9Genes in Mouse Liver

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Abstract
We have studied the roles of estrogen receptor-α (ERα) and the Stat5b form of STAT (signal transducers and activators of transcription) in sex-specific expression ofCyp2a4 (steroid 15α-hydroxylase) andCyp2d9 (steroid 16α-hydroxylase) genes using ERα-deficient mice. ERα deficiency resulted in the repression of the female-specific Cyp2a4 and expression of the male-specific Cyp2d9 genes, respectively in females. In ERα-deficient males, the Cyp2d9 gene continued to be expressed. Nuclear localization of Stat5b occurs in both sexes of ERα-deficient mice, although it is normally observed in only wild-type males. Nuclear localization of Stat5b correlates with the repression of Cyp2a4 and expression ofCyp2d9, respectively. Because Stat5b was not detectable in liver nuclear extracts prepared from hypophysectomized ERα-deficient females, the regulation by ERα appeared to be mediated through a pituitary hormone (i.e., growth hormone). Thus, ERα appears to play a key role in the mechanism that inhibits nuclear localization of Stat5b in female mice, leading to feminization of a ERα-GH-Stat5b pathway and Cyp expression. Defaulting to this ERα-dependent mechanism results in localization of Stat5b to nuclei, which masculinizes the expression of Cyp genes in male mice.