Aggressive behaviors in adult SF-1 knockout mice that are not exposed to gonadal steroids during development.

Abstract

Sex hormones are a major factor responsible for the development of sex differences. Steroidogenic factor 1 (SF-1) is a key regulator of gonadal and adrenal development, and SF-1 knockout mice (SF-1 KO) are born without gonads and adrenal glands. Consequently, these mice are not exposed to gonadal sex steroids. SF-1 KO pups die shortly after birth due to adrenal deficiency. In the present study, SF-1 KO mice were rescued by neonatal corticosteroid injections followed by adrenal transplantations on day 7-8 postnatally. Control mice received corticosteroid injections and were gonadectomized prior to puberty. Mice were observed interacting with ovariectomized hormone primed females and gonad-intact males. In the absence of sex steroid replacement, adult SF-1 KO mice were significantly more aggressive than control mice in tests with stimulus females. After testosterone treatment, control males displayed significantly more aggression towards male intruders than control female mice, or male and female SF-1 KO mice, suggesting a developmental role of gonadal hormones in the expression of aggressive behavior and affirming SF-1 KO mice as a behavioral model to investigate affects of fetal gonad deficiency.Keywords sexual differentiation; VMH; steroidogenic factor 1; sex steroids; aggression Steroidogenic factor 1 (SF-1), officially designated NR5A, was discovered as a regulator of the cytochrome P450 steroidogenic enzymes (Lala, Rice, & Parker, 1992;Morohashi et al., 1994). SF-1 gene expression is restricted to few locations (i.e., gonads, adrenals, pituitary, and the ventromedial nucleus of the hypothalamus [VMH]; Parker et al., 2002). It is an essential factor for gonadal and adrenal development as SF-1 knockout (KO) mice are born without gonads and adrenal glands and have male to female sex reversal (Ingraham et al., 1994;Luo, Ikeda, & Parker, 1994). The structure of the VMH (Dellovade et al., 2000;Ikeda, Luo, Abbud, Nilson, & Parker, 1995;Shinoda et al., 1995) and gene expression in pituitary gonadotropesCorrespondence concerning this article should be addressed to Gregor Majdic, Center for Animal Genomics, Veterinary Faculty, University of Ljubljana, Gerbiceva 60, SI-1000 Ljubljana, Slovenia. E-mail: Gregor.majdic@vf.uni-lj.si. is also markedly altered in SF-1 KO mice (Zhao et al., 2001). Adrenal transplantation rescues these mice so that they can survive to adulthood, and transplanted adrenal glands appear to function normally as corticosterone levels are indistinguishable between adult WT and KO mice (Majdic et al., 2002). With highly selective alterations in VMH organization and lack of developmental exposure to gonadal steroid hormones, SF-1 KO mice provide a potentially important tool for delineating the roles of gonadal hormones and the VMH in a variety of sexdependent aspects of physiology and behavior. NIH Public AccessIn the context of behaviors, male mice castrated on the day of birth display less intermale aggressive behavior than males castrated at PND 10 when treated with androgens in adult life...

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