The Development of Kisspeptin Circuits in the Mammalian Brain - Kisspeptin Signaling in Reproductive Biology - page 228

was specifi cally ablated in kisspeptin neurons
using cre-lox technology (generating “KERKO” mice) in order to test the role of
ER

Finally, in a different study, ER α

signaling in kisspeptin neurons [ 10 ]. In this model, AVPV/PeN kisspeptin-ir
was signifi cantly diminished in adult KERKO females compared to WT females,
further implicating the involvement of E 2 and ER

α

in the development of the AVPV/
PeN kisspeptin population in females [ 10 ]. Likewise, a number of recent studies
have implicated endocrine disruptors (which often mimic the effects of E 2 ) in affect-
ing the development of AVPV/PeN Kiss1 gene expression [ 69 , 95 , 96 ], a topic dis-
cussed in detail in Chap. 21 .

α

The Development of the ARC Kiss1 Population

Ontogeny of Kiss1 Expression in the ARC

The second major population of kisspeptin neurons in the hypothalamus is located
in the ARC, which is equivalent to the INF in humans [ 7 , 14 , 21 , 62 ]. The ARC is
the most consistently detected kisspeptin population in mammalian species,
although its precise distribution and role may vary from species to species [ 15 , 16 ,
19 , 21 , 22 ]. In general, the developmental pattern of Kiss1 expression in the ARC,
and the specifi c factors regulating the development of this neuronal population, are
not completely understood and are less well-characterized than the AVPV/PeN.
Unlike in the AVPV/PeN, Kiss1 is expressed in the rodent ARC during embryonic
development. Analysis of both kisspeptin-ir and Kiss1 mRNA (via qPCR) in embry-
onic rats determined that expression in both sexes begins around E14.5 and increases
by E18.5, with a sharp drop in levels just prior to birth [ 61 ]. Additionally, double-
labeling of kisspeptin-ir/BrdU-ir demonstrated that kisspeptin cell neurogenesis in
the ARC begins around E12.5 and peaks several days later [ 97 ]. In other recent stud-
ies, when crossed to reporter mice that permanently mark all cells that ever expressed
Kiss1 at any point in development, two Kiss1 -Cre transgenic mouse lines were
reported to have “extra” cells in the greater ARC region [ 9 , 11 ]. One of these reports
quantifi ed these “extra” Kiss1 cells to comprise ~25 % of the total cells that have ever
expressed Kiss1 in the ARC region at some point during development or adulthood
[ 11 ]. This suggests that the pattern of ARC kisspeptin expression may differ signifi -
cantly between early developmental and older ages, but it is not clear at what devel-
opmental age these “extra” kisspeptin cells become undetectable. Additionally, both
male and female adult mice with impaired BAX-mediated apoptosis display “extra”
Kiss1 cells in the ARC compared to adult WT mice, particularly in the male, sug-
gesting that the number of ARC Kiss1 neurons is also regulated in early development
by apoptosis [ 40 ]. The extra Kiss1 cells in the ARC of both the Bax KO and the
Kiss1 -Cre mice show a similar expression pattern that is located dorsally in relation
to the normal ARC Kiss1 population (Fig. 11.6 ). The ontogeny, developmental pat-
tern, and role, if any, of these extra kisspeptin neurons remain unknown.