Sexual differentiation of the brain requires perinatal kisspeptin-GnRH neuron signaling.
Sex differences in brain function underlie robust differences between males and females in both normal and disease states. Although alternative mechanisms exist, sexual differentiation of the male mammalian brain is initiated predominantly by testosterone secreted by the testes during the perinatal period. Despite considerable advances in understanding how testosterone and its metabolite estradiol sexually differentiate the brain, little is known about the mechanism that generates the male-specific perinatal testosterone surge. In mice, we show that a male-specific activation of GnRH neurons occurs 0-2 h following birth and that this correlates with the male-specific surge of testosterone occurring up to 5 h after birth. The necessity of GnRH signaling for the sexually differentiating effects of the perinatal testosterone surge was demonstrated by the persistence of female-like brain characteristics in adult male, GnRH receptor knock-out mice. Kisspeptin neurons have recently been identified to be potent, direct activators of GnRH neurons. We demonstrate that a population of kisspeptin neurons appears in the preoptic area of only the male between E19 and P1. The importance of kisspeptin inputs to GnRH neurons for the process of sexual differentiation was demonstrated by the lack of a normal neonatal testosterone surge, and disordered brain sexual differentiation of male mice in which the kisspeptin receptor was deleted selectively from GnRH neurons. These observations demonstrate the necessity of perinatal GnRH signaling for driving brain sexual differentiation and indicate that kisspeptin inputs to GnRH neurons are essential for this process to occur.
Centre for Neuroendocrinology and Department of Physiology, School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand.
Jenny
J
Clarkson
Department of Biology, University of Victoria, Victoria, British Columbia, V8P 5C2 Canada, and.
Ellen R
ER
Busby
Molecular Biology of the Cell, German Cancer Research Centre, 69120 Heidelberg, Germany.
Milen
M
Kirilov
Molecular Biology of the Cell, German Cancer Research Centre, 69120 Heidelberg, Germany.
Günther
G
Schütz
Department of Biology, University of Victoria, Victoria, British Columbia, V8P 5C2 Canada, and.
Nancy M
NM
Sherwood
Centre for Neuroendocrinology and Department of Physiology, School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand, allan.herbison@otago.ac.nz.
Allan E
AE
Herbison
D000818:Animals; D000831:Animals, Newborn; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D011247:Pregnancy; D011301:Preoptic Area / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH / Q000235:genetics / Q000502:physiology; D012727:Sex Characteristics; D012733:Sex Differentiation / Q000502:physiology*; D015398:Signal Transduction; D013739:Testosterone / Q000097:blood; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014667:Vasopressins / Q000378:metabolism
C492248:Kiss1r protein, mouse; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH; D014667:Vasopressins; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D014446:Tyrosine 3-Monooxygenase
GPR54; GnRH; kisspeptin; sexual differentiation; testosterone