ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2006) 11 OC1

Stress response after TIF-2 disruption: loss of grip on feedback control or adrenocortical impairment?

AV Patchev1, D Fischer2, M Herkenham3, F Götz1, SS Wolf5, M Gehin4, P Chambon4, VK Patchev5 & OFX Almeida2

1Institute of Experimental Endocrinology, Humboldt University School of Medicine – Charité Universitätsmedizin Berlin, Berlin, Germany; 2Max Planck Institute of Psychiatry, Munich, Germany; 3Section on Functional Neuroanatomy, NIMH, NIH, Bethesda, MD, United States; 4Institute de Génétique et de Biologie Moléculaire et Céllulaire (IGBMC), Illkirch, France; 5Corporate Research – Gynecology & Andrology, Schering AG/Jenapharm, Jena, Germany.

Efficiency of glucocorticoid receptor (GR) signaling is modulated by a variety of co-activators, including the transcription intermediary factor 2 (TIF-2). Although TIF-2 has been shown to amplify GR signaling in different cellular models and contexts, its system-physiological relevance has not been comprehensively examined. The present work investigated the role of TIF-2 in GR-mediated regulation of hypothalamo-pituitary-adrenal (HPA) axis activity in mice. Experiments were designed to test the hypothesis that ablation of TIF-2 would disrupt the efficacy of GR-mediated control of basal and stress-induced activity at several levels of the HPA axis.

We demonstrate that mice with targeted ablation of TIF-2 show alterations in several mechanisms that control the HPA axis activity under both quiescent conditions and stress. Lack of TIF-2 was associated with increased expression of corticotropin-releasing hormone (CRH) and vasopressin in the hypothalamic paraventricular nucleus and elevated pituitary adrenocorticotropic hormone (ACTH) content, whereas expression of GR mRNA in the hippocampus was decreased. Although these findings are suggestive of impaired HPA axis restraint, TIF-2-deficient animals had lower basal corticosterone levels, and their secretory response to stress was blunted and sluggish. Thus, in TIF-2-knockout mice enhanced central ‘drive’ of the HPA axis is not conveyed into equivalent adrenocortical response. Decreased cellular densities and signs of cytoarchitectonic disorganization in the zona fasciculata of the adrenal cortex suggest that impairment of central HPA regulation in TIF-2-deficient animals is secondary to insidious adrenocortical insufficiency. These data, together with previously described hypogonadism in TIF-2-deficient mice indicate that, besides amplification of nuclear receptor signaling, TIF-2 also appears to be a pre-requisite for normal function of steroid-producing glands.

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