Abstract
Kisspeptin is a potent activator of GnRH-induced gonadotropin secretion and is a proposed central regulator of pubertal onset. In mice, there is a neuroanatomical separation of two discrete kisspeptin neuronal populations, which are sexually dimorphic and are believed to make distinct contributions to reproductive physiology. Within these kisspeptin neuron populations, Kiss1 expression is directly regulated by sex hormones, thereby confounding the roles of sex differences and early activational events that drive the establishment of kisspeptin neurons. In order to better understand sex steroid hormone-dependent and -independent effects on the maturation of kisspeptin neurons, hypogonadal (hpg) mice deficient in GnRH and its downstream effectors were used to determine changes in the developmental kisspeptin expression. In hpg mice, sex differences in Kiss1 mRNA levels and kisspeptin immunoreactivity, typically present at 30 days of age, were absent in the anteroventral periventricular nucleus (AVPV). Although immunoreactive kisspeptin increased from 10 to 30 days of age to levels intermediate between wild type (WT) females and males, corresponding increases in Kiss1 mRNA were not detected. In contrast, the hpg arcuate nucleus (ARC) demonstrated a 10-fold increase in Kiss1 mRNA between 10 and 30 days in both females and males, suggesting that the ARC is a significant center for sex steroid-independent pubertal kisspeptin expression. Interestingly, the normal positive feedback response of AVPV kisspeptin neurons to estrogen observed in WT mice was lost in hpg females, suggesting that exposure to reproductive hormones during development may contribute to the establishment of the ovulatory gonadotropin surge mechanism. Overall, these studies suggest that the onset of pubertal kisspeptin expression is not dependent on reproductive hormones, but that gonadal sex steroids critically shape the hypothalamic kisspeptin neuronal subpopulations to make distinct contributions to the activation and control of the reproductive hormone cascade at the time of puberty.
Highlights
Pubertal maturation and reproductive function rely on the integration of environmental and physiological cues by the GnRH neuronal network [1]
Our results indicate that the developmental changes and sex-based differences in the hypothalamic kisspeptin neuronal network are influenced by both reproductive hormone-dependent and independent mechanisms, and suggest that the arcuate nucleus (ARC) kisspeptin neuronal subpopulation plays an important role in the central activation of the reproductive hormone cascade necessary to initiate puberty
Kisspeptin neurons were identified by immunocytochemistry (ICC) in wild type (WT) mice in both the anteroventral periventricular nucleus (AVPV) and periventricular nucleus (PEN) in the immediate area surrounding the third ventricle, in a rostral-caudal continuum, recently described as the RP3V [17]
Summary
Pubertal maturation and reproductive function rely on the integration of environmental and physiological cues by the GnRH neuronal network [1]. Kisspeptinergic activity satisfies important criteria as a signal necessary for puberty: 1) disruptive mutations and genetic models with ablated kisspeptin signaling are hypogonadal and fail to undergo pubertal maturation [4,5]; 2) at puberty, increased hypothalamic kisspeptin corresponds with the time of increased GnRH release [6,7]; and 3) kisspeptin administration to juvenile animal models elicits precocious activation of the reproductive axis [8]. It remains to be definitively determined whether the kisspeptin system is the driver of hypothalamic-pituitarygonadal (HPG) axis maturation, or rather is dictated, in part or whole, in response to this axis. The influence of the HPG axis itself on the sexual differentiation of hypothalamic kisspeptin organization and function has not been fully elucidated
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