The glucocorticoid receptor regulates transcription through DNA binding as well as through cross-talk with other transcription factors. In hepatocytes, the glucocorticoid receptor is critical for normal postnatal growth. Using hepatocyte-specific and domain-selective mutations in the mouse we show that Stat5 in hepatocytes is essential for normal postnatal growth and that it mediates the growth-promoting effect of the glucocorticoid receptor through a direct interaction involving the Nterminal tetramerization domain of Stat5b. This interaction mediates a selective and unexpectedly extensive part of the transcriptional actions of these molecules since it controls the expression of gene sets involved in growth and sexual maturation.Supplemental material is available at http://www.genesdev.org.Received January 24, 2007; revised version accepted March 16, 2007. Glucocorticoids are secreted by the adrenal cortex and constitute the final effector of the hypothalamus-pituitary-adrenal (HPA) gland axis. They are essential for the maintenance of homeostasis during environmental challenges and are also required for normal development and survival. The effects of glucocorticoids are mediated by the ubiquitously expressed glucocorticoid receptor (GR) and the mineralocorticoid receptor that has a restricted expression. Upon ligand binding, the GR can act in a multitude of ways to induce or repress the transcription of target genes. These ways include binding to glucocorticoid response elements (GREs) in regulatory gene regions and protein-protein interactions with other transcription factors. DNA binding of the GR is believed to mediate most of the activating actions while cross-talk with transcription factors is believed to mediate the repressing actions (Reichardt et al. 1998(Reichardt et al. , 2001. One exception, in which GR activates transcription without classic DNA binding, is its functional interaction with Stat5 (Stocklin et al. 1996). It was originally described for activation of the ␤-casein promoter, where the activation was shown to depend on physical GR-Stat5 interaction and DNA binding of Stat5, whereas GR binding to a classic GRE was dispensable (Stoecklin et al. 1997). In addition, it has been reported that Stat5 can inhibit glucocorticoid-mediated activation of GREs (Stocklin et al. 1996;Biola et al. 2001). However, these studies (Stocklin et al. 1996;Stoecklin et al. 1997;Biola et al. 2001) were carried out in vitro and only investigated the behavior of a few Stat5 target genes.We recently showed that deletion of Nr3c1, the gene encoding GR in hepatocytes leads to a defect in postnatal growth (Tronche et al. 2004). Since Stat5 is a critical link in growth hormone (GH) signaling, it was suggested that this growth deficiency may depend on abrogated Stat5 signaling. Hepatocyte-specific deletion of the genes encoding GR resulted in reduced expression levels of some Stat5 targets regulated by GH, such as insulin-like growth factor-1 (IGF-1) and the acid-labile subunit (ALS) (Tronche et al. 2004). Further...

Mice carrying a hepatocyte-specific inactivation of the glucorticoid receptor (GR) gene show a dramatic reduction in body size. Growth hormone signaling mediated by the Stat5 transcription factors is impaired. We show that Stat5 proteins physically interact with GR and GR is present in vivo on Stat5-dependent IGF-I and ALS regulatory regions. Interestingly, mice with a DNA-binding-deficient GR but an unaltered ability to interact with STAT5 (GR dim/dim ) have a normal body size and normal levels of Stat5-dependent mRNAs. These findings strongly support the model in which GR acts as a coactivator for Stat5-dependent transcription upon GH stimulation and reveal an essential role of hepatic GR in the control of body growth. Received September 8, 2003; revised version accepted January 27, 2004. Glucocorticoids (GCs), which are synthesized in the adrenal cortex, act in many if not all cells of the body and play important roles in development and homeostasis. The effects of the hormone are mediated by the glucocorticoid receptor (GR) that is ubiquitously expressed and by the mineralocorticoid receptor that displays a more restricted expression profile. GR activity depends on the binding of its ligand, which is released on physiological, circadian, and stress stimuli, and thus GR participates in coordinating the organism's responses to the environment. GR can both activate and repress transcription of target genes via DNA binding to glucocorticoid responsive elements (GREs) or cross-talk with other transcription factors (Beato et al. 1995;Tronche et al. 1998). Because the liver is a major target organ for GCs in control of glycogen metabolism and gluconeogenesis, we wished to address the function of hepatic GR by genetic means. As shown previously, loss of the receptor leads to lethality (Cole et al. 1995;Tronche et al. 1998). We therefore have generated cell/tissue-specific and functionselective mutations using the Cre/loxP system Tronche et al. 1999). To define the role of GR in hepatocytes, we expressed the recombinase in hepatocytes under the control of the albumin promoter and the albumin and ␣-fetoprotein enhancers to generate mutant mice with selective inactivation of GR in these cells only (GR AlfpCre mice; Kellendonk et al. 2000). This approach allowed us to partially circumvent the perinatal lethality of GR null mutants. Surprisingly, adult mice with the hepatocyte-specific loss of GR have a severe reduction in body weight. Analysis of these mice revealed not only a novel function of GR in growth control, but also an unprecedented mode of activity. Results and DiscussionApproximately 50% of the homozygous mutants died within 48 h after birth, likely due to the metabolic consequences of the hepatocyte-specific GR knock-out (data not shown). No increase in mortality was observed at later stages. Mice lacking GR in hepatocytes were indistinguishable from their littermates until 3-4 wk of age, but later displayed a severe growth deficit that was more pronounced in adult males than in females (reduction by 32%...

This study provides further evidence that ADR is a frequent cause of admission to medical ICUs resulting in a considerable use of ICU capacities. In the present setting patients with ADR required longer and more intense medical treatment in the ICU than those with deliberate self-poisoning.

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