Model Systems for Studying Kisspeptin Signalling: Mice and Cells - Kisspeptin Signaling in Reproductive Biology - page 475

broadly similar and these have been reviewed previously [ 22 , 23 ]. Small differences
in phenotype are probably due to experimental variation between laboratories. In
summary, mice with global disruption of Kiss1r or Kiss1 are sterile and do not prog-
ress through puberty. Mutant males have small testes, disruption of spermatogenesis
and fail to develop secondary sex glands. Mutant females are acyclic, have thread-
like uteri and small ovaries with no Graafi an follicle or corpus luteum formation.
These effects are caused by low sex steroid and gonadotrophic hormone levels
(hypogonadotrophism). The primary defect in the mutant mice is failure of GnRH
secretion from the median eminence [ 12 ]. In addition, the Kiss1r and Kiss1 mutant
mice cannot activate kisspeptin or GnRH neurons as judged by c - fos induction or
produce the pre-ovulatory LH surge after appropriate hormonal stimulation [ 17 ],
although it has also been reported that the Kiss1r Gt1Stei mice can be induced to show
a modest LH surge [ 30 ]. Most of the data, however, suggest that kisspeptin signal-
ling is also required for normal oestrous cycling and ovulation.
While the phenotypes of the global knock-out mice are generally similar, there are
some subtle differences between Kiss1r and Kiss1 mice, which may be physiologi-
cally informative. The Kiss1 mutant mice have a slightly less severe reproductive
defi cit than the Kiss1r mice. This is most noticeable in males, where the testes,
epididymides and seminal vesicle weights are signifi cantly larger in the Kiss1
mutant mice compared with the Kiss1r mutants and higher numbers of spermatozoa
are found in the vas deferens (Fig. 22.2a-d ) [ 29 , 35 , 36 ]. In addition, the Kiss1
mutant mice show more advanced stages of spermatogenesis than the Kiss1r
mutants, and this is particularly noticeable when the animals are not exposed to
dietary phytoestrogens, which can actually stimulate spermatogenesis in these
mutant mice [ 35 ]. These phenotypic differences are probably related to the slightly
higher levels of both circulating and intratesticular testosterone in the Kiss1 mice
compared with the Kiss1r mice. These data suggest that the Kiss1 mutant mice may
retain some residual signalling through the kisspeptin receptor, which cannot occur
in the Kiss1r mutant mice. Consistent with this hypothesis is the fi nding that the
kisspeptin receptor has around a 5% basal signalling activity in the absence of
ligand binding when expressed in HEK293 cells [ 37 ].
There is also evidence that both the Kiss1 and Kiss1r mutant mice can release low
levels of GnRH from the hypothalamus, which may contribute to their partial sexual
maturation, although they remain infertile. Female mutant mice of either genotype
show periods of vaginal keratinization typically found during oestrous although
ovulations do not occur [ 36 ]. Treatment of mutant females with acyline, a GnRH
antagonist, prevented these periods of keratinization and reduced uterine weights
and LH levels in the blood. In male mice, acyline treatment reduced testicular
weights and LH levels in both Kiss1r and Kiss1 mutants. The ligand-independent
basal activity of the kisspeptin receptor may explain these observations in the Kiss1
mutant mice, but the effects in the Kiss1r mutant mice suggest another pathway for
GnRH release. This is unlikely to be mediated by neurokinin B, as it has been shown
in the Kiss1r tm1.1On mutant mice that this neuropeptide requires the kisspeptin recep-
tor to stimulate LH release [ 28 ]. In contrast, NMDA has been shown to stimulate
GnRH/LH release in Kiss1r mutant mice [ 28 , 38 ] hence the residual GnRH release
may be mediated by ionotropic glutamate neurotransmission.