Kisspeptin and Seasonality of Reproduction - Kisspeptin Signaling in Reproductive Biology - page 401

Introduction

Most subhuman mammals, both domesticated and wild, display seasonality in
reproductive function that is controlled by day length [ 1 ]. In the broadest sense,
animals are either long-day breeders or short-day breeders, such that the reproduc-
tive axis is activated by increasing day length or decreasing day length, respec-
tively. Thus, sheep are short-day breeders whereas hamsters are long-day breeders.
In the simplest terms, day length is “measured” by the perception of light through
the eye, transmitting a signal to the suprachiasmatic nucleus (SCN), which sends
indirect neuronal signals to the pineal gland, which secretes melatonin exclusively
during the hours of darkness (reviewed in refs. [ 2 , 3 ]). Thus, the duration of mela-
tonin secretion, which accurately refl ects the duration of darkness (and hence, the
photoperiod), is the key endogenous signal which induces seasonal changes in
reproductive status. The daily rhythm in CLOCK gene expression within the SCN
is a fundamental driver of this system of detection of day length, leading to a dis-
tinct seasonality of reproduction that is well characterized in hamsters [ 4 ] and
sheep [ 5 , 6 ].
This review focuses on reproductive function, and in this respect, it is important
to note that seasonal change in reproductive function is characterized, in sheep at
least, by a change in the secretion of gonadotropin-releasing hormone (GnRH) [ 7 ].
A nonsteroidal component of the mechanism that causes a fundamental change in
the frequency of luteinizing hormone (LH) pulses was shown in ovariectomized
(OVX) ewes [ 8 ]. Earlier work showed that there is an estrogen-dependent mecha-
nism that also underlies the transition between breeding and nonbreeding seasons,
such that estrogen has a much greater negative feedback effect on the GnRH-
gonadotropin axis in the nonbreeding season [ 9 ]. The sheep is an ideal model for the
collection of hypophyseal portal blood, allowing for the measurement of hypotha-
lamic secretions [ 10 ], and this model was used to show that estrogen acts within the
brain to cause this negative feedback effect [ 11 ]. During the nonbreeding season,
estrogen reduces pulse frequency of GnRH secretion, whereas this does not occur in
the breeding season, at least in sheep [ 12 ]. Herein, we review the evidence that this
seasonally regulated estrogen feedback is mediated through kisspeptin neurons.
Although feedback control of GnRH secretion by gonadal steroids is fundamen-
tal to reproductive function [ 11 , 13 ], GnRH cells do not express estrogen receptor-

α

(ER- α ) [ 14 ], but do express ER β [ 15 ]. Because ER α is the predominant mediator of

the feedback effects of estrogen [ 16 ], other ER -expressing cells in the brain pro-

mulgate the feedback effects of estrogen to the GnRH axis. Although various types
of neurons have been shown to express the relevant sex steroid receptors, a major
conduit for steroid feedback to GnRH cells remained elusive for many years [ 17 ].
The discovery that kisspeptin and its cognate receptor are essential for normal
reproduction [ 18 , 19 ] was a landmark in our understanding of reproductive control,
because kisspeptin cells are highly responsive to gonadal steroid regulation and
appear to transmit feedback signals to GnRH cells. While this does not exclude a
role for other sex steroid receptive neurons, kisspeptin cells appear to be of primary

α