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Insidious adrenocortical insufficiency underlies neuroendocrine dysregulation in TIF-2 deficient mice

Alexandre V. Patchev^*,,1, Dieter Fischer, Siegmund S. Wolf, Miles Herkenham, Franziska Götz^*, Martine Gehin^||, Pierre Chambon^||, Vladimir K. Patchev and Osborne F. X. Almeida

^* Institute of Experimental Endocrinology, Charité School of Medicine, Humboldt University, Berlin, Germany;

Neuroadaptations Group, Max Planck Institute of Psychiatry, Munich, Germany;

Corporate Research Gynecology and Andrology, Schering AG, Jena, Germany;

Section on Functional Neuroanatomy, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA;

^|| Institute de Génétique et de Biologie Moléculaire et Céllulaire (IGBMC), Illkirch, France

¹Correspondence: Institute of Experimental Endocrinology, Charité School of Medicine, Humboldt University, Schumannstr. 20/21, Berlin 10117, Germany. E-mail: alexandre.patchev{at}charite.de

The transcription-intermediary-factor-2 (TIF-2) is a coactivator of the glucocorticoid receptor (GR), and its disruption would be expected to influence glucocorticoid-mediated control of the hypothalamo-pituitary-adrenal (HPA) axis. Here, we show that its targeted deletion in mice is associated with altered expression of several glucocorticoid-dependent components of HPA regulation (e.g., corticotropin-releasing hormone, vasopressin, ACTH, glucocorticoid receptors), suggestive of hyperactivity under basal conditions. At the same time, TIF-2^–/– mice display significantly lower basal corticosterone levels and a sluggish and blunted initial secretory response to brief emotional and prolonged physical stress. Subsequent analysis revealed this discrepancy to result from pronounced aberrations in the structure and function of the adrenal gland, including the cytoarchitectural organization of the zona fasciculata and basal and stress-induced expression of key elements of steroid hormone synthesis, such as the steroidogenic acute regulatory (StAR) protein and 3ß-hydroxysteroid dehydrogenase (3ß-HSD). In addition, altered expression levels of two nuclear receptors, DAX-1 and steroidogenic factor 1 (SF-1), in the adrenal cortex strengthen the view that TIF-2 deletion disrupts adrenocortical development and steroid biosynthesis. Thus, hyperactivity of the hypothalamo-pituitary unit is ascribed to insidious adrenal insufficiency and impaired glucocorticoid feedback.—Patchev, A. V., Fischer, D., Wolf, S. S., Götz, F., Gehin, M., Chambon, P., Patchev, V. K., and Almeida O. F. X. Insidious adrenocortical insufficiency underlies neuroendocrine dysregulation in TIF-2 deficient mice.

Key Words: stress • adrenal cortex • steroidogenesis • hypothalamus • hippocampus