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mechanisms, whose nature has only recently begun to be elucidated
( Lomniczi et al., 2013; Sangiao-Alvarellos et al., 2013 ).
Among the different neuropeptide regulators of GnRH neurons,
kisspeptins have been recognized in recent years as essential signals for the con-
trol of puberty onset and reproductive function ( Navarro & Tena-Sempere,
2012; Pinilla et al., 2012; Roa, Aguilar, et al., 2008; Tena-Sempere, 2008 ).
Kisspeptins are a family of structurally related peptides of different amino acid
length (e.g., Kp-54 and Kp-10) that share the C-terminal region. Kisspeptins
are encoded by the Kiss1 gene and operate through the G protein-coupled
receptor, Gpr54, which is also termed kisspeptin receptor or Kiss1R
( Oakley, Clifton, & Steiner, 2009; Pinilla et al., 2012; Roa, Aguilar, et al.,
2008 ). While kisspeptins were initially identified as metastasis suppressors, in
late 2003 two independent publications first reported the presence of
inactivating mutations of their receptor in patients with isolated hypo-
gonadotropic hypogonadism (HH); a rare condition of lack of puberty and
infertility linked to low gonadotropin and sex steroid levels ( de Roux et al.,
2003; Seminara et al., 2003 ). These initial findings have been recently com-
pleted by the demonstration of the first inactivating mutation of the KISS1
gene in humans with HH ( Topaloglu et al., 2012 ). In good agreement, mice
with inactivation of Gpr54 or Kiss1 genes display a phenotype roughly similar
to that of affected humans ( d'Anglemont de Tassigny et al., 2007; Seminara
et al., 2003 ), thus supporting the conserved role of kisspeptin signaling in
the control of the reproductive axis. This contention has been substantiated
in the last years by a large number of molecular, neuroanatomical, and phys-
iological studies in different species, which have jointly demonstrated that
kisspeptins play an essential role in the direct (and probably indirect) control
of GnRH neurons ( Navarro & Tena-Sempere, 2012; Pinilla et al., 2012 ).
Based on the initial findings that humans and mice lacking functional
Gpr54 or Kiss1 do not display normal pubertal progression, different studies
have addressed the putative physiological roles of kisspeptin signaling in the
timing of puberty; detailed recapitulation of the results of such analyses can
be found elsewhere ( Navarro & Tena-Sempere, 2012; Pinilla et al., 2012 ).
These studies have documented a complex and multifaceted pattern of acti-
vation of the Kiss1 system during the pubertal transition, which seems to
involve, at least, the following major components:
A rise in the hypothalamic expression of Kiss1 and kisspeptin immunore-
active content, which suggests an elevation of the endogenous kisspeptin
toneduring the pubertal transition.As deduced frompharmacological data,
this increase would be sufficient to induce a state of maximal secretory
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