Kisspeptin and Puberty in Mammals - Kisspeptin Signaling in Reproductive Biology - page 251

The developmental pattern of ARC kisspeptin expression as assessed by
immunohistochemistry is less clear. Studies in mice describe an increase in inten-
sity of kisspeptin fi bers in the ARC during postnatal development in both males and
females, but developmental changes in kisspeptin cell number have not been
reported [ 38 , 44 , 45 ]. It is possible that the pubertal increase in kisspeptin fi bers in
the ARC may refl ect an increased kisspeptin output from kisspeptin cell bodies in
the AVPV (see below), as direct innervation of the ARC by AVPV kisspeptin neu-
rons has been reported [ 46 ]. In the ewe, the number of kisspeptin neurons in the
ARC is signifi cantly greater in postpubertal animals compared to prepubertal lambs
[ 47 ]. In the agonadal male monkey, developmental changes in the number of immu-
nopositive kisspeptin neurons in the ARC parallel changes in pulsatile GnRH
release, with both infant and pubertal animals exhibiting numerous and intensely
stained ARC perikarya [ 48 ]. The importance of ARC kisspeptin neuronal network
for generating pulsatile GnRH release in the infant monkey is consistent with the
observation that circulating gonadotropin levels were undetectable in a 2-month old
infantile boy bearing a loss-of-function mutation of KISS1R [ 3 ].
In the case of AVPV kisspeptin neurons, it has been clearly shown that the cell
number in female mice progressively increases until the age of puberty [ 38 , 39 , 44 ,
49 ]. Moreover, the developmental increase in the number of kisspeptin neurons in
the AVPV in females is dependent on the presence of circulating E 2 , as ovariectomy
of prepubertal mice reduces and/or masks this developmental change [ 49 ]. Similarly,
in the hpg mouse, the prepubertal increase in expression of both kisspeptin and
Kiss1 is blunted [ 38 ], and in aromatase knockout mice there is virtually no kiss-
peptin expression [ 49 ]. This action of E 2 appears to be exerted directly on the AVPV
kisspeptin neurons, as conditional knockout of estrogen receptor alpha (ER

)
resulted in a marked decrease in the number of kisspeptin immunopositive neurons
in this nucleus [ 50 ]. Kisspeptin- or KISS1 -expressing neurons have also been
described in the POA of women and female monkeys [ 51 - 53 ], but developmental
changes in this particular population of neurons have not been studied in primates.
Hypothalamic (POA and ARC combined) levels of Kiss1r mRNA increase at the
age of puberty in both male and female rats [ 32 ]. Specifi cally, in the female, Kiss1r
expression in the AVPV increased at the age of puberty [ 33 ]. However, neither the
neuronal phenotype in the POA/AVPV exhibiting this pubertal increase in Kiss1r
expression, nor the gonadal steroid dependency of this phenomenon in rodents, has
been studied. In ovarian intact female rhesus monkeys, KISS1R mRNA in the MBH
also increases across puberty onset [ 43 ], and functionally, developmental changes
in GnRH response to KP-10 depend on the pubertal increase in E 2 (see next section).
Thus, it is possible that the pubertal increase in Kiss1r / KISS1R mRNA in females is
due to the increase in estrogens at this stage of development. However, this view
needs further examination, as KISS1R mRNA expression does not change across
puberty in agonadal male monkeys [ 43 ].
Kiss1r is expressed in approximately 80% of GnRH neurons in cichlid fi sh, and
in adult mice and rats [ 54 - 56 ]. During the fi rst few days of postnatal life in mice,
only ~40% of GnRH neurons express Kiss1r but this increases to adult levels by P20
[ 57 ]. Although expression of KISS1R in primate GnRH neurons has not been

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