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Submitted on October 23, 2006
Accepted on February 8, 2007
Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, MA and Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MD
* To whom correspondence should be addressed. E-mail: djw{at}bu.edu.
Hepatocyte-specific, albumin-Cre-mediated deletion of the entire mouse Stat5a-Stat5b locus was carried out to evaluate the role of STAT5a and STAT5b (STAT5ab) in the sex-dependent transcriptional actions of GH in the liver. The resultant hepatocyte STAT5ab-deficient mice were fertile, and unlike global STAT5b-deficient male mice, postnatal body weight gain was normal, despite a 50% decrease in serum IGF1. Whole liver STAT5ab RNA decreased by 
65-85%, and residual STAT5 immunostaining was observed in a minority of the hepatocytes, indicating incomplete excision by Cre-recombinase. Quantitative PCR analysis of twenty sexually dimorphic, liver-expressed genes revealed significant down-regulation of 10 of 11 male-specific genes in livers of male hepatocyte STAT5ab-deficient mice. Class I female-specific liver genes (Holloway et al (2006) Molec Endocrinol 20: 647-660) were markedly up regulated (de-repressed), whereas the expression of class II female genes, belonging to the Cyp3a subfamily, was unaffected by the loss of hepatocyte STAT5ab. STAT5ab is thus required in the liver for positive regulation of male-specific genes and for negative regulation of a subset of female-specific genes. Continuous GH infusion strongly induced (>500-fold) the class II female gene Cyp3a16 in both wild type and hepatocyte STAT5ab-deficient male mice, indicating sex-specific transcriptional regulation by GH that is STAT5ab-independent. In contrast, hepatocyte STAT5ab deficiency abolished the strong suppression of the male-specific Cyp2d9 by continuous GH seen in control mouse liver. Analysis of global STAT5a-deficient mice indicated no essential requirement of STAT5a for sex-specific liver Cyp expression. Thus, the major loss of liver sexual dimorphism in hepatocyte STAT5ab-deficient mice can primarily be attributed to the loss of STAT5b.
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