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The Journal of Neuroscience, August 15, 2007, 27(33):8826-8835; doi:10.1523/JNEUROSCI.2099-07.2007

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Behavioral/Systems/Cognitive
The Kisspeptin Receptor GPR54 Is Required for Sexual Differentiation of the Brain and Behavior

Alexander S. Kauffman,^1,3 Jin Ho Park,¹ Anika A. McPhie-Lalmansingh,¹ Michelle L. Gottsch,⁴ Cristian Bodo,^1,2 John G. Hohmann,⁵ Maria N. Pavlova,⁵ Alex D. Rohde,⁵ Donald K. Clifton,⁴ Robert A. Steiner,^3,4 and Emilie F. Rissman^1,2

¹Department of Biochemistry and Molecular Genetics and ²Graduate Program in Neuroscience, University of Virginia, Charlottesville, Virginia 22908, Departments of ³Physiology and Biophysics and ⁴Obstetrics and Gynecology, University of Washington, Seattle, Washington 98195, and ⁵Omeros Corporation, Seattle, Washington 98101

Correspondence should be addressed to Dr. Alexander S. Kauffman, Department of Physiology and Biophysics, Health Sciences Building, Box 357290, University of Washington, Seattle, WA 98195-7290. Email: ask47{at}u.washington.edu

GPR54 is a G-protein-coupled receptor, which binds kisspeptins and is widely expressed throughout the brain. Kisspeptin–GPR54 signaling has been implicated in the regulation of pubertal and adulthood gonadotropin-releasing hormone (GnRH) secretion, and mutations or deletions of GPR54 cause hypogonadotropic hypogonadism in humans and mice. Other reproductive roles for kisspeptin–GPR54 signaling, including the regulation of developmental GnRH secretion or sexual behavior in adults, have not yet been explored. Using adult wild-type (WT) and GPR54 knock-out (KO) mice, we first tested whether kisspeptin–GPR54 signaling is necessary for male and female sexual behaviors. We found that hormone-replaced gonadectomized GPR54 KO males and females displayed appropriate gender-specific adult sexual behaviors. Next, we examined whether GPR54 signaling is required for proper display of olfactory-mediated partner preference behavior. Testosterone-treated WT males preferred stimulus females rather than males, whereas similarly treated WT females and GPR54 KO males showed no preference for either sex. Because olfactory preference is sexually dimorphic and organized during development by androgens, we assessed whether GPR54 signaling is essential for sexual differentiation of other sexually dimorphic traits. Interestingly, adult testosterone-treated GPR54 KO males displayed "female-like" numbers of tyrosine hydroxylase-immunoreactive and Kiss1 mRNA-containing neurons in the anteroventral periventricular nucleus and likewise possessed fewer motoneurons in the spino-bulbocavernosus nucleus than did WT males. Our findings indicate that kisspeptin–GPR54 signaling is not required for male or female copulatory behavior, provided there is appropriate adulthood hormone replacement. However, GPR54 is necessary for proper male-like development of several sexually dimorphic traits, likely by regulating GnRH-mediated androgen secretion during "critical windows" in perinatal development.

Key words: metastin; Kiss-1; sexual behavior; olfactory partner preference; SNB motoneuron; AVPV; tyrosine hydroxylase; development; sex differences; hypogonadotropic hypogonadism; GnRH

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Received May 7, 2007; revised June 29, 2007; accepted June 29, 2007.

Correspondence should be addressed to Dr. Alexander S. Kauffman, Department of Physiology and Biophysics, Health Sciences Building, Box 357290, University of Washington, Seattle, WA 98195-7290. Email: ask47{at}u.washington.edu

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