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80% of the kisspeptin neurons in the AVPV also express tyrosine hydroxylase
(indicating the sexually differentiated population of dopaminergic neurons), whereas
no tyrosine hydroxylase co-expression is noted in the ARC [
33
,
74
]. However, lower
Kiss1
-TH co-expression is seen in the AVPV of other species. In the female rat,
kisspeptin neurons in the AVPV and ARC are virtually distinct from TH neurons in
these regions (5-30% of
Kiss1
co-express tyrosine hydroxylase in the rat AVPV)
[
20
]. Similar data are also apparent in the POA and ARC of sheep (
Smith JT
,
unpub-
lished observation
). The distribution of galanin, neurotensin, met-enkephalin
(mENK), and cholecystokinin (CCK)-immunoreactive cells was recently deter-
mined within the AVPV of female mice [
82
]. A small proportion (<10%) of kiss-
peptin cells in the AVPV express galanin whereas a larger percentage (30-40%)
expressed mENK. Interestingly, kisspeptin cells in the ARC had a similar degree of
galanin co-expression but did not co-express mENK [
82
]. Virtually all kisspeptin
neurons in the ARC co-express the NKB and dynorphin, but no kisspeptin neurons
in the AVPV (or POA) do so [
63
,
64
,
83
]. Importantly, ARC kisspeptin cells also
express genes for the NKB receptor (NK3) and the dynorphin receptor [the kappa
opioid receptor (KOR)]. Expression of dynorphin, NKB, KOR, and NK3 is inhibited
by estradiol in the ARC [
64
]. From this, a model whereby NKB and dynorphin act
autosynaptically on kisspeptin neurons in the ARC to potentially shape pulsatile
expression and secretion of kisspeptin has been proposed. This is then thought to
drive the pulsatile release of GnRH from fi bers in the median eminence.
Within kisspeptin neurons, the response to ER
may be regulated by the actions
of SP transcription factor protein complexes. In GT1-7 cells, estradiol increases
Kiss1
promoter activity through the Sp1 binding site at the proximal promoter region
[
84
]. Sp1 and ER
α
form a complex resulting in estrogen-induced activation of the
Kiss1
promoter; however, decreasing the Sp1 to Sp3 ratio negatively regulates
Kiss1
promoter activity [
84
]. A differing Sp1 to Sp3 ratio between the ARC and the AVPV
could potentially explain the differential regulation of
Kiss1
in response to estrogen,
but this remains to be determined. On the other hand, GT1-7 cells are dedifferenti-
ated GnRH cells, so one should be cautious interpreting the relevance of this data.
The presence of
Kiss1
expression in these cells does not match animal data (GnRH
cells do not express
Kiss1
in vivo). Thus, it is possible that aspects of
Kiss1
expres-
sion and regulation in GT1-7 cells do not relate to normal in vivo physiology.
In vivo data suggest it may be differences in estrogen signaling pathways that
defi nes the regulation of kisspeptin. Estrogen can act via ER
α
through multiple
signaling pathways, the major pathways being grouped into classical vs. nonclas-
sical estrogen signaling. Classical signaling involves the translocation of ER
α
into
the nucleus, where it recruits cofactors to the estrogen response element (ERE)
regulatory sites to alter gene transcription, while for nonclassical signaling, the
ER
α
employ ERE-independent genomic pathways that entail interactions with tran-
scription factors. Data from a mouse model, permitting only nonclassical estrogen
signaling, demonstrate that the inhibition of
Kiss1
mRNA in the ARC is mediated
by an ERE-independent ER
α
signaling mechanism—nonclassical estrogen signal-
ing (Fig.
13.6
) [
78
]. Conversely, the stimulation of
Kiss1
in the AVPV is likely to
occur through classical, but not nonclassical, signaling pathways (Fig.
13.6
) [
78
].
α
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