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Physiology Section Department of Cell Biology, Physiology and Immunology University of Córdoba 14004 Córdoba, Spain
Address all correspondence and requests for reprints to: Manuel Tena-Sempere, Physiology Section. Department of Cell Biology, Physiology and Immunology, Faculty of Medicine, University of Córdoba, Avenida Menéndez Pidal s/n, 14004 Córdoba, Spain. E-mail: fi1tesem{at}uco.es.
Reproductive capacity is the common end-point of a series of developmental events and the orchestrated function of a number of regulatory signals, primarily originating from the hypothalamus, the pituitary, and the gonads, which form the so-called gonadotropic axis (1, 2). In this system, pituitary gonadotropins, LH and FSH, are crucial regulators of gonadal maturation and functions, such as ovulation and spermatogenesis. In turn, LH and FSH secretion is controlled by a complex neuroendocrine network integrating central and peripheral signals. The pivotal hierarchical factor in the central control of gonadotropin secretion is the hypothalamic decapeptide GnRH, whose episodic secretion is governed by the interplay of a plethora of excitatory and inhibitory signals at the hypothalamus (3). Among the peripheral factors, gonadal hormones (mainly sex steroids) play an essential role in the self-regulation of the gonadotropic axis, acting at hypothalamic and/or pituitary levels through negative and, eventually positive, feedback loops (1, 2, 3). The functionality of the gonadotropic axis undergoes dramatic changes throughout development and in the adult stage, which ultimately depends on the dynamic interplay of its major regulatory signals, GnRH, LH, FSH, and gonadal hormones, throughout the life span (3). Notably, although the major players of this axis have been known for decades, the precise mechanisms and mediators whereby this functional coupling is conducted remained partially unknown.
In this scenario, a major breakthrough in our understanding on the signals responsible for the functional control of the gonadotropic axis took place by late 2003, when the reproductive facet of the KiSS-1/G protein-coupled receptor 54 (GPR54) system was unraveled on the basis of independent genetic studies by de Roux et al. (4), and Seminara et al. (5). These groups pointed out that inactivating mutations of GPR54 resulted in hypogonadotropic hypogonadism in humans and rodents. These seminal observations drew immediate attention to the ligands of GPR54, a family of structurally related peptides, globally termed kisspeptins, encoded by the previously cloned metastasis-suppressor gene KiSS-1 (6, 7, 8). Thus, kisspeptins, whose major secretory form is a 54-amino acid peptide named metastin after its capacity to inhibit migration in different cancer cell types (6), were immediately suspected as critical regulators of the development and/or function of the gonadotropic system. This contention boosted an extraordinary interest among reproductive physiologists and clinicians, who sought to characterize the role of KiSS-1 system in the physiological control of the reproductive axis. Indeed, in the last few months, several lines of evidence have substantiated the pivotal function of KiSS-1 as major gatekeeper of GnRH neurons and the gonadotropic axis. These included demonstration of the ability of kisspeptins to directly activate GnRH neurons, to induce GnRH secretion, and to potently elicit gonadotropin release in a number of species (mouse, rat, monkey, and sheep) (9, 10, 11, 12, 13, 14, 15, 16, 17, 18). Moreover, hypothalamic expression of KiSS-1 and, to a lesser extent, GPR54 genes, was demonstrated to be developmentally (maximum at puberty) and hormonally regulated (by sex steroids) in the rat and monkey (11, 16). These profiles were enormously suggestive of a key role of KiSS-1 system in puberty onset and feedback control of the gonadotropic axis. However, the original expression analyses suffered from lack of precise anatomical resolution, which hampered the interpretation of the complete physiological relevance of the initial results.
Now, an elegant study by Smith et al., published in this issue of Endocrinology (19), adds further refinement to our knowledge on how KiSS-1 gene is expressed and regulated by sex steroids in the hypothalamus of the female mouse. This paper, together with its counterpart in the male mouse brain, which also recently appeared in Endocrinology (20), provides an exhaustive map of the distribution of KiSS-1 neurons within mouse hypothalamus and sheds light on the precise neuronal networks and molecular mechanisms whereby androgens and estrogens ultimately convey their feedback regulatory actions upon GnRH neurons. These studies describe the prominent expression of KiSS-1 gene in neurons of the arcuate nucleus (Arc) and the anteroventral periventricular hypothalamus (AVPV), and they demonstrate that, whereas KiSS-1 expression in the Arc increases after gonadectomy and decreases after testosterone or estradiol replacement, the KiSS-1 responses to gonadectomy and hormonal substitution are strikingly opposite in the AVPV. Moreover, these studies further confirm the importance of estrogen receptor (ER) 
in conveying the biological actions of estrogen onto this system, whereas the role of ERß appears to be negligible. Taken together with the reported effects of kisspeptins on gonadotropin secretion (9, 10, 11, 12, 13, 14, 15, 16, 17, 18), the well-known feedback actions of sex steroids (1, 2, 3), and the proposed roles of Arc and AVPV in the negative and positive feedback control of gonadotropins, respectively, the data reported by Smith et al. strongly suggest that discrete populations of KiSS-1 neurons within the hypothalamus differentially contribute to the inhibitory and stimulatory feedback effects of gonadal steroids upon GnRH release. Related to this finding, a conspicuous feature of the control of gonadotropin secretion by estrogens is that, despite the prominent role of ER is such a phenomenon, this form of ER is not expressed in GnRH neurons (21, 22). This previous finding pointed out the importance of other sex steroid-sensitive neurons projecting onto GnRH cells, whose nature had remained so far elusive. According to the results of Smith et al., KiSS-1 neurons might qualify as such bridging neurons linking peripheral feedback signals and GnRH-secreting cells.
It is worth noting that the observations of Smith et al., using precise neuroanatomical techniques and different genetically modified mouse models, confirm the original findings on the hormonal regulation of hypothalamic KiSS-1 gene by sex steroids (in the Arc) but at the same time underscore the multifaceted nature of the hypothalamic actions of KiSS-1 in the control of the gonadotropic axis, with apparent opposite roles at the Arc and AVPV. This dichotomy is highly illustrative of the current status and future perspectives of kisspeptin research. Retrospectively considered, it is notable how rapidly our knowledge on the reproductive facets of the KiSS-1 system has evolved in the last few months, providing a reliable platform for further analyses on this system. It is also true, however, that after setting the pillars of the function of KiSS-1 in the neuroendocrine hypothalamus, significant advancements in our understanding of the sites and mechanisms of actions of kisspeptins will require the use of powerful techniques and experimental models, as nicely exemplified in the paper by Smith et al.
In this context, the question arises: where to go for now? Forecasting is tempting. Additional physiological approaches trying to delineate key aspects of kisspeptin function, such as the ontogeny and eventual desensitization of the gonadotropin-releasing actions of this novel system, are still required. However, further research steps in the area must also involve the precise mapping of the networks interacting with KiSS-1 neurons at different hypothalamic nuclei, allowing us to determine the neuronal inputs and projections of KiSS-1 neurons. This neuroanatomical information will be of considerable functional value, and it will help to delineate further experimental testing of the role of kisspeptins in the control of the gonadotropin system (and perhaps eventually other neuroendocrine axes). Tentative approaches for functional assessment might involve the interference or conditional knockout of KiSS-1 (and/or GPR54) gene expression in neurons or specific hypothalamic nuclei in vivo, as well as the electrophysiological characterization of kisspeptin actions onto GnRH-secreting neurons, and the functional properties of KiSS-1 neurons themselves, in vitro. To be noted, important as they are, the available expression data provide only inferential evidence on the actual roles of KiSS-1 in key aspects of gonadotropin control. Presumably, to apply some of the molecular and electrophysiological techniques described above, deeper knowledge of the hypothalamic KiSS-1 system is essential. The contributions of Steiner’s group in this area will certainly prove to be major milestones in the endeavor to enlarge our knowledge of KiSS-1 functions in the control of the reproductive axis.
In summary, during the last few months, KiSS-1 and its receptor GPR54 have been upgraded as masterpieces in the neuroendocrine control of the gonadotropin axis. The data presented by Smith et al. in this issue of Endocrinology (19) further substantiate such a contention, and strongly suggest that KiSS-1 neurons are the long-sought link between peripheral sex steroids and the central GnRH pulse generator, essential for both negative and positive feedback control of gonadotropin secretion. Certainly, elucidation of this and other reproductive aspects of this emergent signal appears as an exceedingly exciting challenge for the near future.
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Received May 31, 2005.
Accepted for publication June 6, 2005.
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