Journal of APPLIED BIOMEDICINE
ISSN 1214-0287 (on-line)
ISSN 1214-021X (printed)
Volume 8 (2010), No 1, p 1-9
DOI 10.2478/v10136-009-0001-0
The kiss-1-kisspeptin-gpr54 complex: a critical modulator of GnRH neurons during pubertal activation
Cesar Alberto Meza-Herrera, Francisco Gerardo Veliz-Deras, Maria Wurzinger, Bernardo Lopez-Ariza, Gerardo Arellano-Rodriguez, Rafael Rodriguez-Martinez
Address: Cesar A. Meza-Herrera, Galeana 585 Poniente, Colonia Centro, Lerdo, Durango, Mexico 35150
cmeza2000@hotmail.com
Received 10th August 2009.
Published online 1st December 2009.
Full text article (pdf)
Abstract in xml format
Summary
Key words
Introduction
Neuroendocrinology of reproduction: Regulation of the Hypothalamic-Hypophyseal-Gonadal Axis
Functional Biology of the Kiss-1, Kisspeptins and GPR54 System
Concluding remarks
References
SUMMARY
Studies have shown that S-nitrosothiols (RSNOs) are able to affect glucose metabolism and blood pressure in animal models. This paper describes an investigation into the effect of two RSNOs, S-nitrosocaptopril (CapSNO) and S-nitroso-N-acetyl-D,L-penicillamine (SNAP) on fasting and postprandial blood glucose concentration, and systolic and diastolic blood pressures. Rats administered intravenously with CapSNO and SNAP, using dosages of 2.0, 5.0 and 12.5 mg/kg BW, showed a dose-dependent hyperglycaemic effect. Intravenous administration of 12.5 mg/kg BW of CapSNO and SNAP caused a statistically significant increase in fasting blood glucose concentration compared to rats treated with the same dosage of captopril. SNAP-treated rats showed a significantly greater elevation of fasting (F2) blood glucose concentration (5.91 ± 0.27 mmol/l) compared to CapSNO-treated rats (5.11 ± 0.08 mmol/l. However there was no significant difference in postprandial blood glucose concentrations. SNAP, CapSNO and captopril significantly reduced both systolic and diastolic blood pressures. This was accompanied by an increase in heart rate. The anti-hypertensive property of CapSNO and SNAP was more significant than that of captopril. CapSNO was more potent than SNAP in reducing blood pressure, suggesting that CapSNO may act via a combined mechanism that involves ACE inhibition and NO release.
KEY WORDS
S-nitrosothiols; S-nitroso-N-acetylpenicillamine; S-nitrosocaptopril; hyperglycaemia; haemodynamic parameters
INTRODUCTION
The onset of the reproductive function in peripuberal
stages and the reproductive capacity in adult stages is
critical to the survival of the species. Therefore,
physiological homeostasis dictates optimal conditions
for reproductive success, and any disturbance of this
balance may affect the function of the gonadotropin
releasing hormone (GnRH) neurones (Meza-Herrera
et al. 2009). These perturbations may include
alterations in the signals dictated by stress, nutritional
imbalance, body weight and some neurological
alterations. For these reasons, changes in other
neuroendocrine systems may directly influence the
hypothalamic-hypophyseal-gonadal axis, through
direct regulation of GnRH (Belsham and Lovejoy
2005, Ebling 2005, Maffucci and Gore 2009).
Certainly, the establishment of the pubertal
process does not only depend on chronological age
(Bronson 2001, DiVall and Radovick 2009). Rather,
the neurotransmitter and neuromodulatory systems
that regulate GnRH secretion and release, also relay
on information about metabolic fuels, body energy
reserves, somatic development and, for many species,
information about season and social environment
(Teresawa and Fernandez 2001, Arechiga-Flores et al.
2004, Meza-Herrera et al. 2009, Veliz et al. 2009).
Clear links exist between metabolic fuel (glucose,
pyruvate and lactate) availability and the reproductive
function (Cheung et al. 1997, Ebling 2005).
In fact, changes in the blood levels of metabolic
hormones are important signals that inform the
nutritional status of mammals (Meza-Herrera et al.
2007, 2008, Gamez-Vazquez et al. 2008). An
explanation is that the response to a feed
supplementation alters glucose, insulin, leptin or
IGF-I and probably other metabolic hormones
(Meza-Herrera et al. 2004, 2008, 2009,
Munoz-Gutierrez et al. 2005, Scaramuzzi et al. 2006,
Guerra-Garcia et al. 2009).
Nonetheless, activation of the
hypothalamic-hypophyseal-gonadal axis is a required
step in order for puberty to occur. Secretion of GnRH
is significantly reduced before puberty. Certainly, in
the early stages of the puberty process, the
hypothalamic gonadostat is still depressed while the
amplitude of GnRH pulses is increasing. Later on, the
concentration of the gonadotropic follicle stimulating
(FSH) and luteinizing (LH) hormones, gradually
increases as puberty advances. This gonadotropic
input stimulates follicular growth and maturation
while oestrogen production by the ovaries also
increases (Apter 1997, Roth et al. 2001, Apter and
Hermanson 2002, Aparicio 2005).
The extremely efficient negative feedback system
from the ovarian steroids is particularly active before
the puberal process begins. Nonetheless, as the
puberal stage advances, a highly efficient positive
feedback signal from the ovarian steroids is activated,
promoting the establishment of normal cyclicity by
the end of this stage. Because of that, an efficient
transition from the prepubertal stage to total
maturation at puberty is an indispensable prerequisite
for the establishment of the reproductive function
(Aparicio 2005, Teresawa 2005, Clarkson and
Herbison 2006, Messinis 2006, Ojeda et al. 2006a, b,
DiVall and Radovick 2009).
The aim of this review is to highlight the
endocrine and genetic discoveries involved in the
establishment of the hypothalamic-hypophyseal-gonadal axis function which promotes
the onset of the reproductive function during puberty.
To accomplish that, some basic aspects of the
function of the hypothalamic-hypophyseal-gonadal
axis, as well as of the role of the novel system
kisspeptins (KP) and their cognate receptor GPR54
acting as critical regulators of the onset of puberty
will be discussed. This review includes recent
advances in the molecular consequences of KP action
on GnRH neurons as well as comments how these
neuronal circuits are integrated.
NEUROENDOCRINOLOGY OF REPRODUCTION: REGULATION OF THE HYPOTHALAMIC-HYPOPHYSEAL-GONADAL AXIS
The GnRH pulse generator and gonadotrophin
release: Overview and recent insights
The initiation of the reproductive function is a
centrally regulated process and the detailed
mechanisms of its function are still unknown. It is
recognized, however, that increases in the activity of
the pulse generator of the GnRH, and then in the
pulsatile secretion of gonadotrophins FSH and LH
take place. During puberty, the pulsatile secretion of
gonadotrophin is increased during the day, promoting
normal gonadal development and function; the latter
because of the activation of the GnRH pulse generator
(Aparicio 2005, Teresawa 2005, Clarkson and
Herbison 2006, Messinis 2006, Ojeda et al. 2006a,
Prevot et al. 2007).
GnRH is a decapeptide mainly synthesized in the
preoptic area (POA) and the mediobasal (MB)
hypothalamus. Up to sixteen different forms of GnRH
have been isolated (Latimer et al. 2000) and the
amino acid sequence of the hypophysiotrophic GnRH
(pGlu-His-Trp-Ser-Tyr-Gly-Len-Ser-Pro-Gly-NH2)
has been found almost identical in most mammals
(Ramakrishnappa et al. 2005), with the exception of
the guinea pig (Jimenez-Linan et al. 1997). Only a
few GnRH neurons, scattered through the POA and
adjacent areas with an estimated total population of
2,400 GnRH cells have been reported in the adult
brain (Marshal and Goldsmith 1980, Clarke and
Pompolo 2005).
Ontogeny of GnRH neuron development in the
brain
According to Wray (2001), the GnRH neurons
originate from the olfactory placode of the embryo,
later on, the cells migrate to and colonize the basal
forebrain, around the POA, and the mediobasal
hypothalamus. Some studies have demonstrated that
the largest GnRH concentration is found in the
median eminence (ME) of the mammalian species,
where it is stored in neuronal terminals prior to
release into the hypophyseal portal blood (Lehman et
al. 1986, Clarke and Pompolo 2005), although a
discrete number of GnRH cells in the arcuate nucleus
may be relevant to the basal secretion of this peptide
in sheep (Boukhliq et al. 1999).
As mentioned by Clarke and Pompolo (2005), the
anatomical connections between the hypothalamus,
median eminence and the hypophysis can be
considered a masterpiece of design which allows an
exquisite control of the gonadotropes in the pituitary.
In fact, GnRH neurons project to the
external-secretory zone of the ME, where terminals
gain a close proximity to the capillary bed of the
hypophyseal portal system (Clarke and Pompolo
2005). Changes in the pattern release of GnRH will
determine, in turn, the onset of puberty as well as the
maintenance of the reproductive function in the adult
state. According to Heger et al. (2007), transsynaptic
changes involve a coordinated increase in excitatory
inputs but a reduction in inhibitory influences
(Teresawa and Fernandez 2001). In the same way, the
glial component of this neuronal system is mainly
facilitatory and exerts its actions through growth
factors upon GnRH secretion (Prevot et al. 2007).
Extra-hypothalamic GnRH and GnRH receptor
expression in different tissues
Interestingly, although the hypothalamus and pituitary
are the principal source and target site for GnRH,
several reports have recently suggested
extra-hypothalamic GnRH and GnRH receptors in
various tissues such as ovaries (follicle and corpus
luteum), uterus, placenta, endometrium, oviducts,
testes, prostate and mammary glands
(Ramakrishnappa et al. 2005, Singh et al. 2008). The
presence of GnRH-R in these tissues is intriguing and
warrants the evaluation of a functional role of this
ligand-receptor system in the regulation of the
reproductive process.
Functional biology of GnRH neurones upon the
hypothalamic-hypophyseal axis
In adult animals, GnRH is released in a pulsatile
fashion, every 60 min, inside the portal system which
connect to the hypophysis. In young animals,
however, the pulse interval is much more larger, 90 to
120 minutes, and it is the acceleration of the
frequency of the pulse and the increase in the
amplitude of the pulse, as well as the total GnRH
concentration, that activates transduction signals to
promote both synthesis and intermittent release of LH
and FSH, generating the onset of the pubertal process
(Aparicio 2005, Teresawa 2005, Clarkson and
Herbison 2006, Messinis 2006, Ojeda et al. 2006a).
In the gonadotrope, GnRH binds to a single class
of G protein coupled receptor, which is a member of
the large superfamily of seven transmembrane domain
receptors that bind to G proteins (Ramakrishnappa et
al. 2005) and initiates a series of physiological events
leading to the synthesis and release of LH and FSH.
Upon binding to its receptor, GnRH activates the
enzyme phospholipase-C, via the generation of
different second messengers such as dyacilglycerol
and inositol. Then, the activation of protein kinase-C
and the release of Ca from the intracellular space
occur, generating both the synthesis and the secretion
of LH and FSH. The GnRH-R expression is regulated
by the GnRH itself as well as by gonadal steroids
(Apter 1997, Roth et al. 2001, Apter and Hermanson
2003, Ramakrishnappa et al. 2005, Clarkson and
Herbison 2006, Messinis 2006, Ojeda et al. 2006a).
The GnRH system at prepuberal and peripuberal
stages
Prior to puberty, GnRH secretion is markedly
suppressed, while at the beginning of puberty, the
hypothalamic gonadostat is also depressed and the
amplitude of the GnRH pulses increases. The
hormonal level of LH and FSH are gradually
increased during puberty, stimulating both follicular
maturation and ovarian oestrogen production. The
negative feedback of oestradiol is powerful only prior
to puberty, while the oestradiol positive feedback is
turned on for the first time at the end of puberty. As
a result, the normal cyclicity of the ovarian function
is established so that steroidal and non-steroidal
hormones mediate the effect of the ovaries upon the
hypothalamic-hypophyseal system. Both, oestradiol
and progesterone are important regulators of the FSH
and LH secretion, while inhibin plays a paramount
role in the control of FSH secretion (Apter 1997,
Aparicio 2005, Clarke and Pompolo 2005, Clarkson
and Herbison 2006, Messinis 2006).
The neurons releasing GnRH, represent the
critical cellular type that, once activated, induce
puberty (Clarkson and Herbison 2006). For this
reason, an appropriate expression of the GnRH-R in
the gonadotrophs is critical for the signalling and
secretion of gonadotrophins in order to mediate, in
this way, ulterior sexual development
(Zapatero-Caballero et al. 2004). The GnRH neurons
are important not only because they are involved in
the onset of the reproductive function, but also in the
development of neuromodulatory functions in the
adult (Aparicio 2005, Clarke and Pompolo 2005,
Whitlock et al. 2006).
The discovery of the ligand activator of the
signalling upstream route from GnRH linked to the
G-protein receptor gives more significance to the
central role that the hypothalamus plays in the
regulation of puberty (Clarkson and Herbison 2006,
Hughes and Kumanan 2006). The onset of puberty is
associated with an increase in the amplitude and
frequency of LH. Later on, a progressive increase in
the LH pulsatility occurs during the day, while a
progressive reduction is observed of the amplification
which previously occurred during the night. In
females, prepubertal FSH concentrations are
relatively high, and a continuous process of follicular
development and atresia occurs, observing relatively
high concentrations of oestradiol. Ovarian
steroidogenesis is activated only after this initial
increase in LH, leading to increases in oestrogen
secretion. Thereafter, both follicular development and
maturation occur, under FSH stimulation (Apter 1997,
Suttie et al. 1998, Aparicio 2005).
FUNCTIONAL BIOLOGY OF THE KiSS-1, KISSPEPTINS AND GPR54 SYSTEM
The KiSS-1, KP and GPR54 system: A basic approach
The hypothalamic gene KiSS1, encodes a 54 amino
acid precursor that is cleaved to a family of peptides
known as kisspeptins, also known as metastin, (Popa
et al. 2005, Brown et al. 2008) and has been
considered as an essential integrator of peripheral
cues including the gonadal steroids as well as
nutritional status, which act, in turn, upon the
activation of GnRH neurons (Aparicio 2005, Popa et
al. 2005, Tena-Sempere 2006 a, b, c). Kisspeptin and
its receptor GPR54 which is linked to G-proteins,
have emerged as key elements in the regulation of
GnRH secretion (Aparicio 2005, Gottsch et al. 2006,
Tena-Sempere 2006a, b, c, DiVall and Radovick
2009).
Since GPR54 mutations do not prevent the
migration of GnRH neurons from the olfactory
placode to the forebrain, it is suggested that GPR54 is
required for the normal physiological function of
GnRH neurons after they have migrated and
innervated their targets (Popa et al. 2005). The
GPR54 gene is expressed in several peripheral tissues
such as the placenta, pancreas, kidney, testis, anterior
pituitary, and the brain, most notably the
hypothalamus, preoptic area (POA), midbrain,
hippocampus, amygdala and medulla (Lee et al.
1999, Kotani et al. 2001, Muir et al. 2001).
The KiSS-1, KP & GPR54 system and the reproductive brain
Kisspeptins were originally identified as tumoral
metastasis suppressor peptides bound to the G-protein
linked GPR54 receptor (Castellano et al. 2006a, b,
Ojeda et al. 2006b). However, mutations in the
GPR54 gene have been related to an absence in the
onset of puberty and hypogonadotrophic
hypogonadism (Castellano et al. 2006a, b,
Tena-Sempere, 2006c). The proteolytic cleavage of
the KiSS1 primary product generates the decapeptide
kisspeptin-10, which is the minimal kisspeptin
sequence necessary for receptor activation, has shown
itself to be a very potent agent promoting LH release
(Ojeda et al. 2006b, Kadokawa et al. 2008, Suzuki et
al. 2008) and which has also demonstrated direct
action upon the secretion of GH and PRL from
cultured bovine pituitary cells (Kadokawa et al.
2008).
KiSS1 mRNA has been detected in several
peripheral sites including the hypothalamus,
hypophysis, ovary, placenta and adipose tissue
(Castellano et al. 2006a, b, Gutierrez-Pascual et al.
2007, Brown et al. 2008). Since GPR54 is highly
expressed in the pituitary gland (Gutierrez-Pascual et
al. 2007), kisspeptin should be secreted from
kisspeptin neurons into the hypophyseal portal blood
to act on the hypophysis, and may also exert autocrine
and paracrine actions in the pituitary (Kadokawa et al.
2008).
An element involved in synapses formation,
SynCAM, is an immunoglobulin-like adhesion
molecule previously recognized as a tumour
suppressor molecule in lung cancer. It has been
proposed that both SynCAM and kisspeptin conform
a network of genes which, besides their function as
suppressor molecules of tumoral metastasis in the
brain, also act as integrator elements in
neuron-to-neuron and glia-to-neuron communication,
building a functional unit able to initiate the puberty
process (Ojeda et al. 2006b).
The KiSS-1, KP, GPR54 complex: A signalling system modulating the onset of puberty
Hypogonadotrophic hypogonadism has been observed
when mutations in the GPR54 receptor expression
occur, indicating that signalling through this receptor
is a prerequisite for sexual maturation. The central
administration of kisspeptin stimulates secretion of
both GnRH and gonadotrophins in prepubertal and
adult animals. In the same way, increases in the
expression of the KiSS1 and GPR54 genes have been
observed during the pubertal development, while
activation of GPR54 by kisspeptin administration is
enough to induce the activation of the gonadotrophic
axis in immature animals (Aparicio 2005, Popa et al.
2005, Gottsch et al. 2006, Tena-Sempere 2006a, b).
Neurons expressing kisspeptin are direct targets of
the steroid feedback action, both positive and
negative, which differently regulate the mRNA KiSS1
expression in several brain areas, and have again a
relevant role in the establishment of puberty. It has
been suggested that there is a double site of kisspeptin
action in the brain, either in the
hypothalamic-hypophyseal region or in the median
eminence, an area located outside the blood brain
barrier.
The available data suggest that kisspeptins are
synthesized in neurons located in the anteroventral
periventricular nucleus and the arcuate nucleus. Both
populations are considered to be involved in the
control of gonadotropes. Besides that, KP nerve
terminals and receptors are found in other
hypothalamic areas suggesting that KP could be
involved in the regulation of other yet unknown
homeostatic or neuroendocrine functions (Mikkelsen
and Simonneaux 2009). In addition, KP-neurons have
been located in discrete subsets of the preoptic area
and the arquate nuclei of the brain; those neurons
containing the GPR54 receptors are more diffusely
distributed and include GnRH neurons as well as the
adenohypophysis. In primates, the KiSS1 and GPR54
mRNA levels significantly increase in the
hypothalamus at the time of puberty suggesting that
an increase in the GPR54 mediated signal contributes
to the pubertal activation of GnRH secretion (Ojeda
et al. 2006b).
Prior to puberty, a pulsatile increase in GnRH
secretion is observed due to coordinated changes in
the trans-synaptic communication and to the
interaction between neuron-to-glial cells. As the
excitatory signal from neurons and glial cells
increases, a reduction in the inhibition in the
trans-synaptic tone is observed, generating the
pubertal activation of GnRH secretion. The neuronal
systems more invoked in this process include
glutamate and the peptide kisspeptin which exert
neurotransmission and neuromodulation processes,
while the most important inhibitory signal is provided
by GABAtergic and opiatergic neurons (Ojeda et al.
2006b).
Glial cells and GnRH neurons display a
morphologic and functional relationship which
depends on growth factors that act through
serine-treonine-kinase receptors as the transforming
growth factor (TGFB1). These growth factors send
their signal through receptors with tyrosine-kinase
activity such as the insulin-like growth factors
(IGF-1), the fibroblast growth factor, the members of
the epidermal growth factor family, the TGFalfa and
the neuregulins. A complete discussion on the roles of
these growth factors has been previously presented by
Garcia-Segura and McCarthy (2004), Gill et al.
(2004), and Ojeda (2006a, b).
The KiSS-1, KP and GPR54 system: A sensory system to translate environmental cues
KiSS1 is also involved in the metabolic control of the
reproductive function; the expression of the
hypothalamic gene KiSS1 is negatively regulated
under conditions of negative energy balance, and
administration of kisspeptin is capable of reversing
the hypogonadotrophic stage observed under
scenarios of undernutrition and metabolic disturbance
(Aparicio 2005, Castellano et al. 2005, Tena-Sempere
2006b, Brown et al. 2008).
Besides nutritional status, the photoperiod input is
another of the most influential environmental cues
modulating seasonal reproduction. In fact, in
mammals, an environmental photoperiod is
transduced by a photoneuroendocrine system
composed of the retina, the suprachiasmic nucleus,
and the pineal gland (Goldman 2001). The last of
these releases the hormone melatonin exclusively at
night so that the duration of secretion varies
according to day length acting as the neurochemical
expression of time (Goldman 2001, Simonneaux and
Ribelayga 2003). In turn, melatonin modulates
reproduction by regulating GnRH secretion, without
acting directly upon the GnRH neurons (Malpaux et
al. 2001). Instead, the mid-hypothalamus has been
proposed as the site for melatonin action on
reproduction, which is compatible with the
localization of KiSS1 expression (Smith et al. 2005).
According to Clark et al. (2009), in seasonal
breeders such as sheep, KP expression in the arcuate
nucleus is markedly reduced during the non-breeding
season, a physiological scenario which strongly
suggests that the mechanisms that control seasonal
changes in reproductive function involve KP-neurons.
Since the non-breeding season is characterized by
increased negative feedback of oestrogen on GnRH
secretion, KP-neurons seem to be involved in the
breeding status of seasonal-breeders.
In this respect, Revel et al. (2006) reported a
significant role for the KiSS1/kisspeptin/GPR54
system in the control of seasonal reproduction,
suggesting that the photoperiod, via melatonin
secretion, modulates KiSS1 signalling to drive the
reproductive axis. Certainly, according to Roseweir
and Millar (2009), the KP-GPR54 complex has a great
ability to co-ordinate mediation of many important
signals relayed to the GnRH neuron such as positive
and negative feedback, metabolic input and
photoperiod; integrating in this way, signals from
both internal and external sources.
According to Roa and Tena-Sempere (2007),
while the characterization of the KiSS-1/GPR54
system in the control of essential aspects of female
reproduction, from puberty to ovulation in
mammalian species, has been extensively reported, its
role in non-mammalian species remains largely
unexplored. In this respect, Carrillo et al. (2009)
reported the presence of GPR54 in GnRH neurons
and changes in its expression during pubertal
maturation in perciform fish species (sea bass), which
is suggestive of a conserved function of this system
during the evolution process of different species.
Stronger evidence points to the KiSS-1-KP-GPR54
complex signalling as the main trigger of GnRH
neuron activation and subsequent ovulation.
Therefore, elucidation of the action pathways of this
complex should generate new pharmacalogic
strategies both for fertility and contraception
treatments in the near future (Sills and Walsh 2008).
Puberty is a developmental process that culminates in
the acquisition of reproductive capability. This
process is initiated with the release of GnRH from
specialized hypothalamic neurons to stimulate
hormonal cascades as well as gonadal activation.
GnRH neurons are reasonably mature at birth, but, as
the growth process starts, the pulsatile release of
GnRH is suppressed. Later on, as the prepubertal
phase approaches, inhibitory signals are diminished,
while an increase in the pulsatile release of GnRH is
observed. The last scenario results in a cascade of
events with increases in synthesis and release of the
hypophyseal gonadotrophins, LH and FSH, as well as
an increase in ovarian function, particularly
steroidogenesis and gametogenesis.
One of the most frequently invoked excitatory
neuronal systems, for the neurotransmission and
neuromodulatory processes during the establishment
of the reproductive function is the kisspeptin and its
GPR54 receptor. KP binds to its G-protein-coupled
receptor GPR54, expressed in GnRH neurons,
stimulating GnRH release and activation of the
reproductive axis. Certainly, KP has been universally
recognized as essential activator of the gonadotropic
axis, with key roles in the onset of puberty as well as
in the control of gonadotrophin secretion. Besides
that, novel aspects of the KiSS-1, KP and GPR54
complex have pointed to this complex as a very
effective sensory system which translates
environmental cues into endocrine responses. The last
includes its potential involvement in the
neuroendocrine control of seasonal reproduction as
well as acting as a metabolic gate for reproductive
function, integrating in this way signals from internal
and external environments. These novel actions of the
KiSS-1-KP-GPR54 complex acquire particular
importance in the design of new reproductive and
nutritional management technologies in seasonal
breeders, such as sheep and goats, as well as in animal
production systems under marginal conditions.
Interestingly, the expression of KiSS-1, mRNA
and peptide, and its GPR54 receptor has recently been
reported in the mammalian ovary, as well as in the
establishment of the reproductive function in fish
species. The last adds complexity to the potential
action of this system in female reproduction in several
species, emerging as a highly conserved reproductive
system throughout the evolutionary process of
multiple species. Understanding the reproductive axis,
its development, activation and maintenance, has
proved to be an important yet difficult assignment,
due to the many regulatory components of this
system. Further studies designed to elucidate the
kisspeptin dependent-neural regulation of
hypothalamic GnRH neurons, should gain new
insights to better understand the establishment of the
pubertal process, an exciting research area in both
human and animal reproductive biology and
neuroendocrinology.
ACKNOWLEDGMENT
This review was prepared within the outlined actions
of the International Collaborative Projects
"CONACYT-FOMIX-DURANGO,
DGO-2008-C01-87559", funded by the National
Council of Science and Technology, Mexico, as well
as "ALFA-III-ALAS, DCI-ALA/A9.09.01
/08/19189/161-358/ALFA-III-82", supported by the
European Union. The authors acknowledge financial
support from these projects.
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