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Pre-B-Cell Transcription Factor 1 and Steroidogenic Factor 1 Synergistically Regulate Adrenocortical Growth and Steroidogenesis

Department of Internal Medicine II (U.D.L., M.D., D.M.S., F.B.), Division of Endocrinology and Metabolism; Department of Internal Medicine I and Center for Clinical Trials (M.D., M.K., T.Z., J.S.S.); and Department of Pharmacology I (J.S.S.), Albert-Ludwigs-University Freiburg, D-79104 Freiburg, Germany; Research Institute for the Biology of Farm Animals (A.H.), Research Unit Genetics and Biometry, D-18196 Dummerstorf, Germany; Department of Internal Medicine (S.H.), Endocrine and Diabetes Unit, University of Wuerzburg, D-97074 Wuerzburg, Germany; Division of Metabolism, Endocrinology, and Diabetes (T.E., G.D.H.), Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109; School of Animal and Microbial Sciences (A.B.B.), University of Reading, Reading RG6 6AH, United Kingdom; Division of Endocrinology and Metabolism (N.R.S.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Pathology (M.P.K.), University of California San Diego, School of Medicine, La Jolla, California 92093; and Division of Endocrine Research (F.B.), Department of Medicine Innenstadt, Ludwig-Maximilians-University, D-80336 Munich, Germany

Address all correspondence and requests for reprints to: Felix Beuschlein, M.D., Division of Endocrine Research, Department of Medicine Innenstadt, University Hospital Munich, Ziemssenstrasse 1, D-80336 Munich, Germany. E-mail: felix.beuschlein{at}med.uni-muenchen.de.

A variety of transcription factors including Wilms tumor gene (Wt-1), steroidogenic factor 1 (Sf-1), dosage-sensitive sex reversal, adrenal hypoplasia congenita on the X-chromosome, Gene 1 (Dax-1), and pre-B-cell transcription factor 1 (Pbx1) have been defined as necessary for regular adrenocortical development. However, the role of Pbx1 for adrenal growth and function in the adult organism together with the molecular relationship between Pbx1 and these other transcription factors have not been characterized. We demonstrate that Pbx haploinsufficiency (Pbx1^+/–) in mice is accompanied by a significant lower adrenal weight in adult animals compared with wild-type controls. Accordingly, baseline proliferating cell nuclear antigen levels are lower in Pbx1^+/– mice, and unilateral adrenalectomy results in impaired contralateral compensatory adrenal growth, indicating a lower proliferative potential in the context of Pbx1 haploinsufficiency. In accordance with the key role of IGFs in adrenocortical proliferation and development, real-time RT-PCR demonstrates significant lower expression levels of the IGF-I receptor, and up-regulation of IGF binding protein-2. Functionally, Pbx1^+/– mice display a blunted corticosterone response after ACTH stimulation coincident with lower adrenal expression of the ACTH receptor (melanocortin 2 receptor, Mc2-r). Mechanistically, in vitro studies reveal that Pbx1 and Sf-1 synergistically stimulates Mc2-r promoter activity. Moreover, Sf-1 directly activates the Pbx1 promoter activity in vitro and in vivo. Taken together, these studies provide evidence for a role of Pbx1 in the maintenance of a functional adrenal cortex mediated by synergistic actions of Pbx1 and Sf-1 in the transcriptional regulation of the critical effector of adrenocortical differentiation, the ACTH receptor.