title: Insidious adrenocortical insufficiency underlies neuroendocrine dysregulation in TIF-2 deficient mice.
abstract: 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 3beta-hydroxysteroid dehydrogenase (3beta-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.
authors.affiliation: Institute of Experimental Endocrinology, Charité School of Medicine, Humboldt University, Schumannstr. 20/21, Berlin 10117, Germany. alexandre.patchev@charite.de
authors.forename: Alexandre V
authors.initials: AV
authors.lastname: Patchev
authors.forename: Dieter
authors.initials: D
authors.lastname: Fischer
authors.forename: Siegmund S
authors.initials: SS
authors.lastname: Wolf
authors.forename: Miles
authors.initials: M
authors.lastname: Herkenham
authors.forename: Franziska
authors.initials: F
authors.lastname: Götz
authors.forename: Martine
authors.initials: M
authors.lastname: Gehin
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Vladimir K
authors.initials: VK
authors.lastname: Patchev
authors.forename: Osborne F X
authors.initials: OF
authors.lastname: Almeida
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000302:Adrenal Cortex / Q000503:physiopathology*; D000818:Animals; D001483:Base Sequence; D003345:Corticosterone / Q000097:blood; D017931:DNA Primers; D005260:Female; D007030:Hypothalamo-Hypophyseal System; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051958:Nuclear Receptor Coactivator 2; D010750:Phosphoproteins / Q000378:metabolism; D010913:Pituitary-Adrenal System; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054339:Steroidogenic Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D017931:DNA Primers; C498002:Ncoa2 protein, mouse; D051958:Nuclear Receptor Coactivator 2; D010750:Phosphoproteins; D011965:Receptors, Glucocorticoid; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; D000098682:Steroidogenic Acute Regulatory Protein; C515058:steroidogenic factor 1, mouse; D015096:3-Hydroxysteroid Dehydrogenases; D003345:Corticosterone