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Central Nervous System-Specific Knockout of Steroidogenic Factor 1 Results in Increased Anxiety-Like Behavior

Departments of Internal Medicine and Pharmacology (L.Z., K.W.K., K.K.A., S.C., K.L.P.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-8857; Department of Histology and Cytology (Y.I.), Yokohama City University School of Medicine, Yokohama 236-0004, Japan; and Department of Biomedical Sciences (L.B., S.C., S.A.T.), Colorado State University, Fort Collins, Colorado 80523-1617

Address all correspondence and requests for reprints to: Keith L. Parker, University of Texas Southwestern/Room Y5.224, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8857. E-mail: keith.parker{at}utsouthwestern.edu.

Steroidogenic factor 1 (SF-1) plays key roles in adrenal and gonadal development, expression of pituitary gonadotropins, and development of the ventromedial hypothalamic nucleus (VMH). If kept alive by adrenal transplants, global knockout (KO) mice lacking SF-1 exhibit delayed-onset obesity and decreased locomotor activity. To define specific roles of SF-1 in the VMH, we used the Cre-loxP system to inactivate SF-1 in a central nervous system (CNS)-specific manner. These mice largely recapitulated the VMH structural defect seen in mice lacking SF-1 in all tissues. In multiple behavioral tests, mice with CNS-specific KO of SF-1 had significantly more anxiety-like behavior than wild-type littermates. The CNS-specific SF-1 KO mice had diminished expression or altered distribution in the mediobasal hypothalamus of several genes whose expression has been linked to stress and anxiety-like behavior, including brain-derived neurotrophic factor, the type 2 receptor for CRH (Crhr2), and Ucn 3. Moreover, transfection and EMSAs support a direct role of SF-1 in Crhr2 regulation. These findings reveal important roles of SF-1 in the hypothalamic expression of key regulators of anxiety-like behavior, providing a plausible molecular basis for the behavioral effect of CNS-specific KO of this nuclear receptor.

NURSA Molecule Pages Link:

Nuclear Receptors:   SF-1

Ligands:   17β-Estradiol

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