This Article Full Text Full Text (PDF) All Versions of this Article: 148/5/1977    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Holloway, M. G. Articles by Waxman, D. J. Search for Related Content PubMed PubMed Citation Articles by Holloway, M. G. Articles by Waxman, D. J.

Loss of Sexually Dimorphic Liver Gene Expression upon Hepatocyte-Specific Deletion of Stat5a-Stat5b Locus

Division of Cell and Molecular Biology (M.G.H., E.V.L., D.J.W.), Department of Biology, Boston University, Boston, Massachusetts 02215; and Laboratory of Genetics and Physiology (Y.C., A.H., L.H.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence to: David J. Waxman, Department of Biology, Boston University, 5 Cummington Street, Boston, Massachusetts 02215. E-mail: djw{at}bu.edu.

Hepatocyte-specific, albumin-Cre recombinase-mediated deletion of the entire mouse Stat5a-Stat5b locus was carried out to evaluate the role of signal transducer and activator of transcription 5a and 5b (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 IGF-I. Whole-liver STAT5ab RNA decreased by approximately 65–85%, and residual STAT5 immunostaining was observed in a minority of the hepatocytes, indicating incomplete excision by Cre-recombinase. Quantitative PCR analysis of 20 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 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 expression of these sex-specific liver Cyp genes. Thus, the major loss of liver sexual dimorphism in hepatocyte STAT5ab-deficient mice can primarily be attributed to the loss of STAT5b.

This article has been cited by other articles:

				A. Hosui and L. Hennighausen Genomic dissection of the cytokine-controlled STAT5 signaling network in liver Physiol Genomics, July 9, 2008; 34(2): 135 - 143. [Abstract] [Full Text] [PDF]

				T. Hashita, T. Sakuma, M. Akada, A. Nakajima, H. Yamahara, S. Ito, H. Takesako, and N. Nemoto Forkhead Box A2-Mediated Regulation of Female-Predominant Expression of the Mouse Cyp2b9 Gene Drug Metab. Dispos., June 1, 2008; 36(6): 1080 - 1087. [Abstract] [Full Text] [PDF]

				M. G. Holloway, G. D. Miles, A. A. Dombkowski, and D. J. Waxman Liver-Specific Hepatocyte Nuclear Factor-4{alpha} Deficiency: Greater Impact on Gene Expression in Male than in Female Mouse Liver Mol. Endocrinol., May 1, 2008; 22(5): 1274 - 1286. [Abstract] [Full Text] [PDF]

				K. H. Clodfelter, G. D. Miles, V. Wauthier, M. G. Holloway, X. Zhang, P. Hodor, W. J. Ray, and D. J. Waxman Role of STAT5a in regulation of sex-specific gene expression in female but not male mouse liver revealed by microarray analysis Physiol Genomics, September 11, 2007; 31(1): 63 - 74. [Abstract] [Full Text] [PDF]