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In fact, in the same study, it was demonstrated that timed elimination of
Kiss1 neurons during the early juvenile period prevented normal pubertal
maturation and caused infertility (
Mayer & Boehm, 2011
). In fact, a similar
phenomenon has been previously proposed also for GnRH, that is, that a
congenital residual set of GnRH neurons might be sufficient to drive
puberty onset, because of the occurrence of compensatory fail-safe
(
Herbison, Porteous, Pape, Mora, & Hurst, 2008
). In fact, those findings
further document the complex pattern of developmental regulation of Kiss1
neurons that, despite potential compensatory mechanism, are essential for
the timed activation of the HPG axis that leads to puberty.
3. PUTATIVE ROLES OF KISSPEPTIN PARTNERS
IN THE CONTROL OF PUBERTY: THE CASE OF NKB
Besides the demonstration of the important roles of kisspeptins in the
control of puberty and fertility, significant efforts have been devoted recently
to elucidate the major regulatory signals whereby the different Kiss1 neuro-
nal populations are specifically controlled in different developmental periods
and functional states of the HPG axis (
Lehman, Coolen, &Goodman, 2010
).
In this context, anatomical analysis have demonstrated that at least an impor-
tant fraction of Kiss1 neurons in the ARC, but not in the RP3V, coexpress
neurokinin B (NKB) and its receptor (NK3R) (
Navarro & Tena-Sempere,
2012
). The physiological (and translational) relevance of this phenomenon is
suggested by the finding that humans with inactivating mutations of the
NKB or NK3R gene display a state of HH similar to that of
GPR54
or
KISS1
mutants (
Topaloglu et al., 2009; Young et al., 2010
). In the same
vein, mouse lines with defective NKB signaling have been shown to display
reduced fertility and some degree of impairment of gonadotropin function
(
Yang, Caligioni, Chan, & Seminara, 2012
), although the rodent phenotype
seems to be less dramatic than in humans. Of note, the coexpression of NKB
and kisspeptins in the ARC have been documented in numerous species,
including sheep (
Goodman et al., 2007
), goat, mouse (
Navarro, Gottsch,
et al., 2009; Wakabayashi et al., 2010
), rat (
Burke, Letts, Krajewski, &
Rance, 2006
), and monkey (
Ramaswamy et al., 2010
). Yet, a recent report
suggested that a fraction of kisspeptin and NKB immune reactivity does not
appear to colocalize in the infundibular area of the hypothalamus of young
men (
Hrabovszky et al., 2012
). Yet, even in that study, as much as 75% of
kisspeptin-positive perikarya showed also distinctive NKB expression. To
add further complexity to the system, the expression of dynorphin-A
