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pathway of apoptosis was ruled out [ 40 ]. This model predicts that the differences in
sex steroid exposure between male and female rodent brains early in neonatal life
eventually result in permanent changes in the transcriptional activity of the Kiss1
gene in the AVPV/PeN, resulting in greater Kiss1 silencing in males and greater
transcriptional activation in females. Supporting this, DNA methylation of the puta-
tive promoter of the Kiss1 gene in the AVPV/PeN is sexually differentiated [ 83 ],
though we still do not know when or how in development this Kiss1 methylation
difference fi rst occurs.
Although E 2 signaling in males masculinizes the AVPV/PeN Kiss1 system dur-
ing the neonatal “critical period,” it now appears that exposure to E 2 in developing
females also shapes and promotes the complete feminization of AVPV/PeN Kiss1
expression [ 10 , 62 , 94 ]. Indeed, several studies in mice have suggested that E 2 is
required at some time during development in order for AVPV/PeN kisspeptin
expression to fully develop a female phenotype [ 10 , 62 , 94 ]. However, the mecha-
nism by which this occurs currently remains a mystery and may also involve epi-
genetics, neurogenesis, or a combination of these and other processes.
The role of the ARC/INF population of kisspeptin neurons in mediating sex ste-
roid negative feedback in rodents appears to be different than some other mammals,
such as sheep, in which ARC kisspeptin cells also play a role in positive feedback.
Recent studies suggest that Kiss1 is expressed in the ARC of developing rodents
long before the AVPV/PeN, including prenatally (Fig. 11.10 ). The role of ARC
Kiss1 expression during prenatal/neonatal development is currently unknown and
requires further investigation. In many species, the regulation of ARC kisspeptin
fi bers and their projections in development remains under-studied, in part because,
until recently, there has not been a good way to distinguish the anatomical origin of
kisspeptin-ir fi bers. The recent fi ndings that the ARC Kiss1 population co-expresses
NKB and DYN (in all species examined to date), whereas AVPV/PeN Kiss1 neurons
do not, should facilitate future studies characterizing the development of kisspeptin
neuron projections, as should the use of several newly created transgenic Kiss1
mouse models. Additionally, some studies suggest that there may be an increase in
Kiss1 expression in the ARC around puberty (Fig. 11.10 ), but the data is incomplete
and inconsistent between studies, and more experiments looking at pubertal Kiss1 /
kisspeptin expression with higher temporal resolution are needed, including in non-
rodent species.
While sex differences in ARC Kiss1 cell number have not been observed by most
studies examining adult rodents, such sex differences do exist in the ARC of neona-
tal and juvenile rodents (Fig. 11.10 ), as do sex differences in the gonad hormone-
independent regulation of ARC Kiss1 neurons in prepubertal life, at least in mice.
The functional signifi cance of these early ARC Kiss1 sex differences is unknown,
as are the specifi c factors controlling Kiss1 expression in the ARC at early develop-
mental ages. For example, sex steroids may transiently inhibit ARC Kiss1 neurons
(activational effects) during prenatal and postnatal development, as occurs in adult-
hood, but this has not been directly tested. Indeed, there is a need for examination
of normal sex steroid levels in developing rodents, especially mice, during neonatal,
juvenile, and prepubertal stages. Interestingly, it appears that in the complete
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