Model Systems for Studying Kisspeptin Signalling: Mice and Cells - Kisspeptin Signaling in Reproductive Biology - page 470

Introduction
Mammalian fertility is regulated by neuroendocrine signals in the hypothalamus
that integrate hormonal, metabolic and environmental cues with activation of the
reproductive axis. Gonadotropin releasing hormone (GnRH) neurons are vital for
the normal function of the reproductive axis as they release GnRH into the hypoph-
yseal portal system to stimulate gonadotrophic hormone secretion from the anterior
pituitary gland. The gonadotrophic hormones, luteinizing hormone (LH) and
follicle-stimulating hormone (FSH), act on the gonads to increase sex steroid pro-
duction required for gametogenesis, ovulation and normal fertility.
Kisspeptin and its G-protein coupled receptor (KISS1R or GPR54) are required
for central activation of the hypothalamic pituitary-gonadal axis at puberty and reg-
ulation of reproductive function in many species, including mammals [ 1 , 2 ].
Kisspeptins are produced by the Kiss1 gene, which encodes a 145 or 138 amino-
acid precursor protein in humans, depending upon a frameshift polymorphism, that
is cleaved into overlapping C-terminal amidated peptides (KP54, KP14, KP13 and
KP10) with similar binding affi nities for the kisspeptin receptor [ 3 - 5 ].
Kisspeptins are expressed predominantly in two discrete neuronal populations in
the rodent hypothalamus, the anterioventral periventricular nucleus (AVPV) and the
arcuate nucleus (ARC) [ 6 ]. Kisspeptin neurons make close contact with GnRH neu-
rons [ 7 ], which express the kisspeptin receptor [ 8 , 9 ], and kisspeptin is a potent
stimulator of GnRH release [ 10 - 12 ]. The kisspeptin neurons in the AVPV region
are sexually dimorphic, with a greater number in female rodents [ 13 , 14 ]. Kisspeptin
expression is increased in AVPV neurons in response to rising oestrogen levels [ 15 ],
which stimulate the GnRH/LH surge required for ovulation [ 16 , 17 ]. In contrast,
kisspeptin expression in ARC neurons is negatively regulated by oestrogen and
testosterone [ 15 , 18 ]. This differential regulation of kisspeptin expression by sex
steroids indicates a clear biological difference between AVPV and ARC Kiss1
neurons. It is generally accepted that the AVPV Kiss1 neurons are involved in gen-
erating the ovulatory LH surge, while the ARC Kiss1 neurons may act as a GnRH
pulse generator [ 19 ]. This pacemaker activity of ARC Kiss1 neurons is currently
thought to be controlled by an interplay between neurokinin B (NKB) and dynor-
phin, two neuropeptides that are produced by Kiss1 neurons in the ARC, but not in
the AVPV region [ 20 , 21 ].
Transgenic Mice Generation
Mice with specifi c alterations to their genome are a powerful tool to study the func-
tion of a protein in the context of the whole animal [ 22 , 23 ]. Understanding the
complex neuronal circuitry and the neuropeptides and neurotransmitters that con-
trol the reproductive axis requires studying an intact system. There is conservation
of function in the reproductive and neuroendocrine systems between mice and other
mammalian species which allows gene function to be assessed in a whole animal