Evidence of a Role for Kisspeptin and Neurokinin B in Puberty of Female Sheep

Abstract

Puberty onset in female sheep is marked by a decrease in estradiol-negative feedback, allowing for the increase in GnRH and LH pulses that heralds the first ovulation. Based on recent genetic studies in humans, two possible neuropeptides that could promote puberty onset are kisspeptin and neurokinin B (NKB). Our first experiment determined whether the NKB agonist, senktide, could stimulate LH secretion in prepubertal ewes. A second study used prepubertal and postpubertal ewes that were intact or ovariectomized (OVX) to test the hypothesis that expression of kisspeptin and NKB in the arcuate nucleus increased postpubertally. For comparison, kisspeptin and NKB expression in age-matched intact, and castrated males were also examined. In experiment 1, the percentage of ewes showing an LH pulse immediately after injection of senktide (100 μg, 60%; 500 μg, 100%) was greater than that for water-injected controls (experiment 1a, 25%; experiment 1b, 20%). In experiment 2, kisspeptin-positive cell numbers in the arcuate nucleus increased after puberty in intact females and were increased by OVX in prepubertal but not postpubertal ewes. Changes in kisspeptin cell numbers were paralleled by changes in kisspeptin-close contacts onto GnRH neurons in the medial preoptic area. NKB cell numbers did not differ significantly between intact prepubertal and postpubertal ewes but increased with OVX in both age groups. NKB fiber immunoreactivity was greater in postpubertal than in prepubertal intact ewes. In age-matched males, kisspeptin and NKB cell numbers increased with castration, but decreased with age. These results support the hypothesis that kisspeptin is a gatekeeper to female ovine puberty and raise the possibility that NKB may also play a role, albeit through different means.

Effects of NELL2 on the regulation of GnRH expression and puberty in female rats

“…At 45 days, GnRH expression was similar in all groups, despite the reduced NELL2 expression observed. This finding is consistent with the hypothesis that the synthesis and release of GnRH is regulated not only by NELL2, but also by other factors such as kisspeptin and neurokinin B Plant et al, 2006;Wakabayashi et al, 2010;Nestor et al, 2012). We hypothesized that after long-term NELL2 suppression, kisspeptin and neurokinin B may compensate to promote the synthesis and release of GnRH, which would in turn activate the hypothalamus-pituitary-gonad axis to initiate sexual maturation.…”

Localization of kisspeptin neurons in the hypothalamus of peripubertal female lambs; possible connection with gonadotrophin releasing hormone and neuropeptide Y neurons

“…The most apparent centre was located in the ARC nucleus and this is in line with data obtained in adult sheep (Franceschini et al, 2006;Nestor et al, 2012), horses (Decourt et al, 2008), rodents Herbison, 2006 andmonkeys (Ramaswamy et al, 2008). A similar distribution of kpir perikarya and fibres in the hypothalamus has been described in ewes in the luteal phase of their oestrous cycle after colchicine treatment (Franceschini et al, 2006).…”

“…Our ongoing experiment on growing lambs shows, however, that the number of positive kpir cells in this nucleus of the hypothalamus gradually increases from a few visible cells/section in 5-week-old lambs up to almost seventy cells/section in 16-week-old ones (to be published). Recent data obtained on prepubertal (5-to 6-month-old) and post pubertal (9-month-old) female lambs also showed a predominant population of kp perikarya in the ARC nucleus that increased with age (Nestor et al, 2012). The expression of Kiss1 mRNA is also activated in the ARC nucleus of ewe lambs during juvenile development from 25-35 weeks of age (Redmond et al, 2011).…”

ENDOCRINOLOGY AND ADOLESCENCE: Deciphering puberty: novel partners, novel mechanisms

“…Considering the relevant role of NKB signaling in the central control of the reproductive axis, the involvement of NKB in the onset of puberty has begun to be evaluated recently; yet, the number of studies on this particular area remains scarce (39,41,42). Notwithstanding, our data on immature rats demonstrate that, like adult, cyclic females, prepubertal female rats are able to respond to the NKB agonist, senktide, with robust LH responses (41).…”

“…Indeed, comparison of expression profiles of NKB and Kiss1 genes in the hypothalamus of female rats during postnatal development would suggest that the rise of NKB expression anticipates the elevation of Kiss1 mRNA levels, a phenomenon that has been recently documented in the mouse (43), and whose functional implications are yet to be elucidated. In the same vein, a modulatory role of NKB signaling on puberty has been very recently proposed in the female sheep (42), in which increased NKB fiber immunoreactivity, but not cell numbers, was detected in post-pubertal vs prepubertal ewes. One interesting issue that warrants investigation is the potential sexual dimorphism in the roles of NKB in the control of puberty, at least in some species, as our recent data suggest that LH responses to senktide are lower in magnitude in male vs female rats before puberty, and, in contrast to females, they become null in male rats during the pubertal transition to adulthood (39).…”