Sexual Differentiation of Kiss1 Gene Expression in the Brain of the Rat

Abstract

The Kiss1 gene codes for kisspeptins, which have been implicated in the neuroendocrine regulation of reproduction. In the brain, Kiss1 mRNA-expressing neurons are located in the arcuate (ARC) and anteroventral periventricular (AVPV) nuclei. Kiss1 neurons in the AVPV appear to play a role in generating the preovulatory GnRH/LH surge, which occurs only in females and is organized perinatally by gonadal steroids. Because Kiss1 is involved in the sexually dimorphic GnRH/LH surge, we hypothesized that Kiss1 expression is sexually differentiated, with females having more Kiss1 neurons than either males or neonatally androgenized females. To test this, male and female rats were neonatally treated with androgen or vehicle; then, as adults, they were left intact or gonadectomized and implanted with capsules containing sex steroids or nothing. Kiss1 mRNA levels in the AVPV and ARC were determined by in situ hybridization. Normal females expressed significantly more Kiss1 mRNA in the AVPV than normal males, even under identical adult hormonal conditions. This Kiss1 sex difference was organized perinatally, as demonstrated by the observation that neonatally androgenized females displayed a male-like pattern of adulthood Kiss1 expression in the AVPV. In contrast, there was neither a sex difference nor an influence of neonatal treatment on Kiss1 expression in the ARC. Using double-labeling techniques, we determined that the sexually differentiated Kiss1 neurons in the AVPV are distinct from the sexually differentiated population of tyrosine hydroxylase (dopaminergic) neurons in this region. Our findings suggest that sex differences in kisspeptin signaling from the AVPV subserve the cellular mechanisms controlling the sexually differentiated GnRH/LH surge.

Hypothalamic control of the male neonatal testosterone surge

“…Subsequent studies by Gill et al [59] have demonstrated that the sexual differentiation of kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V) is disrupted in the hpg mouse ( figure 3). Normally, neonatal testosterone exposure acts to reduce the number of kisspeptin-expressing neurons in the RP3V of the male to approximately 10% of that observed in females [60,61]. In the hpg mouse, the number of kisspeptin neurons in the male RP3V is not masculinized, with a greater number of neurons compared with wild-type (figure 3), resulting in similar numbers of kisspeptin neurons in the RP3V of male and female hpg mice.…”

“…The neonatal testosterone surge drives programmed cell death [31] to generate the sexual dimorphic features of the RP3V. Thus, in generating the testosterone surge, the neonatal RP3V kisspeptin neurons initiate a sequence of events that leads to their own demise as potential kisspeptin neurons are killed in the male to generate the 10-fold female-dominant number of kisspeptin neurons within the RP3V [61,78].…”

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…Extensive experimental studies in various species have demonstrated that kisspeptin-producing neurons are major afferents to GnRH neurons and are essential for different aspects of GnRH function, ranging from the tonic feedback control of GnRH and/or gonadotropin secretion to generation of the pre-ovulatory surge responsible for ovulation. 43 Interestingly, although kisspeptins do not seem to be mandatory for proper GnRH neuron migration, compelling experimental work has documented that populations of kisspeptin neurons undergo a dynamic process of prenatal and postnatal maturation that enables them to establish connections with GnRH neurons early in development 44 (under the control of steroid hormones [45][46][47] ). Similarly, identification of mutations in TAC3 (encoding tachykinin-3, which is cleaved to form neurokinin-B) and TACR3 (encoding tachykinin receptor 3; also known as neuromedin-K receptor [NKR]) [48][49][50] in patients with CHH highlights the important role of members of the tachykinin family in the control of GnRH neurons.…”

Histone modifications proposed to regulate sexual differentiation of brain and behavior

“…The sex differences found in dimorphic brain structures are not uniform in nature: some result from disproportion in cell numbers and some arise from the differences in synaptic connections or neuropil density; dimorphisms in chemical characteristics of cells and arborization have also been described [52, [69][70][71][72][73]. Moreover, most dimorphic nuclei described in rodent species are larger in males with the exception of anteroventral periventricular nucleus (AVPV), which is larger in females [70].…”

“…Moreover, most dimorphic nuclei described in rodent species are larger in males with the exception of anteroventral periventricular nucleus (AVPV), which is larger in females [70]. Notably the difference in AVPV between the sexes is revealed in the density of cells as well as in their chemical characteristics: females have many more dopaminergic [74] and about ten times more kisspeptinexpressing neurons [71,75], which project to and stimulate gonadotropin-releasing hormone (GnRH) neurons triggering the luteinizing hormone (LH) surge [76,77]. Thus, the higher number of kisspeptin neurons in the female AVPV may have direct physiological consequences and explain the sex difference in the induction of LH surges, as males do not show this neuroendocrine response.…”