Impaired male sexual behavior in activin receptor type II knockout mice.
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.
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ABSTRACT: Approximately 80 million people worldwide are infertile, and nearly half of all infertility cases are attributed to a male factor. Therefore, progress in reproductive genetics becomes crucial for future diagnosis and treatment of infertility. In recent years, enormous progress has been made in this field. More than 400 mutant mouse models with specific reproductive abnormalities have been produced, and numerous human association studies have been discovered. However, the translation of basic science findings to clinical practice remains protracted, with only modest progress in the application of novel findings to clinical genetic testing and cures. To date, the most significant findings in male infertility remain numeric and structural chromosomal abnormalities and Y-chromosome microdeletions in infertile men. Thus, we anticipate that future genetic investigations will focus on infertile men with a normal somatic karyotype but with various spermatozoal defects, like insufficient production of spermatozoa (oligozoospermia), inadequate motility (asthenozoospermia), abnormal morphology (teratozoospermia), or combinations of these defects. Ultimately, basic advances in mammalian nonhuman reproduction will translate to clinical advances in human reproduction and testing for infertile humans, thereby helping to improve diagnostics and health care for infertile patients.Journal of Andrology 10/2009; 31(1):34-44. · 2.97 Impact Factor
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ABSTRACT: A plethora of discoveries relating to sex influences on brain function is rapidly moving this field into the spotlight for most areas of neuroscience. The domain of molecular or genetic neuroscience is no exception. The goal of this article is to highlight key developments concerning sex-based dimorphisms in molecular neuroscience, describe control mechanisms regulating these differences, address the implications of these dimorphisms for normal and abnormal brain function and discuss what these advances mean for future work in the field. The overriding conclusion is that, as for neuroscience in general, molecular neuroscience has to take into account potential sex influences that might modify signalling pathways.Nature Reviews Neuroscience 01/2010; 11(1):9-17. · 26.48 Impact Factor