Loss of Sexually Dimorphic Liver Gene Expression upon Hepatocyte-Specific Deletion of Stat5a-Stat5b Locus
Open Access
- 1 May 2007
- journal article
- other
- Published by The Endocrine Society in Endocrinology
- Vol. 148 (5), 1977-1986
- https://doi.org/10.1210/en.2006-1419
Abstract
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.Keywords
This publication has 38 references indexed in Scilit:
- Clarifying the role of Stat5 in lymphoid development and Abelson-induced transformationBlood, 2006
- Characterization of Distinct Stat5b Binding Sites That Mediate Growth Hormone-stimulated IGF-I Gene TranscriptionPublished by Elsevier BV ,2006
- Identification of a Distal STAT5-binding DNA Region That May Mediate Growth Hormone Regulation of Insulin-like Growth Factor-I Gene ExpressionPublished by Elsevier BV ,2005
- Hypothalamic STAT Proteins: Regulation of Somatostatin Neurones by Growth Hormone Via STAT5bJournal of Neuroendocrinology, 2005
- The homeobox transcription factor Prox1 is highly conserved in embryonic hepatoblasts and in adult and transformed hepatocytes, but is absent from bile duct epitheliumBrain Structure and Function, 2004
- Signaling pathways activated by the growth hormone receptorTrends in Endocrinology & Metabolism, 2001
- STAT5b-deficient Mice Are Growth Hormone Pulse-resistantPublished by Elsevier BV ,1999
- Distinctive Roles of STAT5a and STAT5b in Sexual Dimorphism of Hepatic P450 Gene ExpressionPublished by Elsevier BV ,1999
- STATs and Gene RegulationScience, 1997
- Sex differences in the ultradian pattern of plasma growth hormone concentrations in miceJournal of Endocrinology, 1991