Immortalised neurons as a model to study the signals involved in the migration of gonadotropin-releasing hormone (GnRH) neurons: basic and clinical implications

Reproduction is the key function for the propagation of the species and requires a correct development and maturation of the gonads, as well as of the neuroendocrine control, exerted mainly by the action of GnRH-secreting neurons. Among hypothalamic neuroendocrine neurons, GnRH cells represent a unique class: they are generated in the olfactory placode from which they move to the septal-hypothalamic region by tangential neurophilic migration along the terminal and the vomeronasal nerves. Once the final destination has been reached, GnRH neurons undergo final differentiation and axonal elongation to make contacts with the pituitary portal vessels in the median eminence; they then start releasing GnRH in a pulsatile fashion, to modulate the secretion of pituitary gonadotropins. The migration of GnRH neurons is under the strict control of several developmental cues; their defect might represent a cause of clinical disorders, as the Kallmann’s syndrome (KS) and the hypogonadotropic hypogonadisms (HH). The development of two cell lines of immortalized GnRH neurons (GT1 and GN) allowed for an accurate study of the mechanisms controlling the synthesis and the secretion of GnRH. These cell lines, obtained in mice by genetic targeted tumorigenesis, retain many of the phenotypic characteristics of GnRH neurons. Of interest, GT1 cells derive from a hypothalamic tumour, while GN cells were obtained from a tumour localized in the olfactory bulb. The different origin of these cell lines leads to the hypothesis that they might represent hypothalamic post-migratory neurons (GT1 cells), or GnRH neurons blocked at an early stage of their migration (GN cells). Using different experimental procedures, we have demonstrated that the two cell subclones GT1-7 and GN11 show a different morphology and express a different migratory behaviour in vitro. These results suggest that the use of GN11 cells may represent an experimental tool to screen the factors possibly involved in the control of the migratory processes of GnRH neurons.