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Impaired Male Sexual Behavior in Activin Receptor Type II Knockout Mice¹

Departments of Pathology,³ Molecular and Cellular Biology,⁴ and Molecular and Human Genetics,⁵ Baylor College of Medicine, Houston, Texas 77030 Department of Molecular and Integrative Physiology,⁶ University of Kansas Medical Center, Kansas City, Kansas 66160

ABSTRACT

Integration of multiple hormonal and neuronal signaling pathways in the medial preoptic area (mPOA) is required for elicitation of male sexual behavior in most vertebrates. Perturbation of nitric oxide synthase (NOS) activity in the mPOA causes significant defects in male sexual behavior. Although activins and their signaling components are highly expressed throughout the brain, including the mPOA, their functional significance in the central nervous system (CNS) is unknown. Here, we demonstrate a neurophysiologic role for activin signaling in male reproductive behavior. Adult activin receptor type II null (Acvr2^–/–) male mice display multiple reproductive behavioral deficits, including delayed initiation of copulation, reduced mount, and intromission frequencies, and increased mount, intromission, and ejaculation latencies. These behavioral defects in the adult mice are independent of gonadotropin-releasing hormone (GnRH) homeostasis or mating-induced changes in luteinizing hormone (LH) and testosterone levels. The impairment in behavior can be correlated to the nitric oxide content in the CNS because Acvr2^–/– males have decreased NOS activity in the mPOA but not the rest of the hypothalamus or cortex. Olfactory acuity tests confirmed that Acvr2^–/– mice have no defects in general odor or pheromone recognition. In addition, motor functions are not impaired and the mutants demonstrate normal neuromuscular coordination and balance. Furthermore, the penile histology in mutant mice appears normal, with no significant differences in the expression of penile differentiation marker genes compared with controls, suggesting the observed behavioral phenotypes are not due to structural defects in the penis. Our studies identify a previously unrecognized role of activin signaling in male sexual behavior and suggest that activins and/or related family members are upstream regulators of NOS activity within the mPOA of the forebrain.

activin, androgen receptor, behavior, gonadotropin-releasing hormone, hypothalamus, male sexual behavior, male sexual function, NOS, steroids, testosterone

¹ Supported in part by The Moran Foundation (T.R.K.), Department of Pathology, Baylor College of Medicine (T.R.K.), National Institutes of Health grants MH57442 and MH63954 (S.K.M.), and HD32067 (M.M.M.) and the National Institutes of Health Specialized Cooperative Centers Program in Reproduction Research (HD07495). The Ligand and Hormone Assay Core at University of Charlottesville, Virginia is supported by an NIH grant (U-54-HD28–394) to the Center for Cellular and Molecular Studies in Reproduction.

² Correspondence. FAX: 913 588 0455; tkumar{at}kumc.edu

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