Cell-Based Models to Study GnRH Neuron Physiology

The chance to produce in vitro cultures of neuronal cells has been fundamental for biological studies. The advancing of our understanding on the physiology of the nervous system has been strongly supported by the in vitro cultures of neuronal cells, as both primary cultures and oncogene-mediated immortalized cells. Among the hypothalamic neuroendocrine neurons, gonadotropin-releasing hormone (GnRH) expressing neurons represent a unique class; they are generated outside the brain, in the olfactory placode, and during embryonic life they move by tangential neurophilic migration, along terminal and vomeronasal nerves, to the septal-hypothalamic region. At this level GnRH neurons undergo terminal differentiation and axonal elongation to make contacts with the pituitary portal vessels in which they start releasing the decapeptide GnRH in a pulsatile fashion, to modulate the function of the reproductive axis. However, the investigation of GnRH neurons has been hindered by their low abundance (800-1200) and their peculiar anatomical distribution. The study of these neurons has been forwarded since '90 by the availability of cell lines of immortalized mouse GnRH-expressing neurons (GT1 and GN cells lines); more later, other cell lines of GnRH-releasing neurons were established from human fetal olfactory neuroblasts and rat adult hypothalamic neurons under conditional immortalization. Later, different in vitro models for the study of GnRH neurons have been described; they include organotypic cultures of olfactory placode or hypothalamic tissue and primary cultures enriched in GnRH neurons. More recently, an new in vitro model of GnRH neurons has been obtained from primary human fetal hypothalamic cell cultures. A new impulse to the study of these peculiar neurons in physiological, as well as in pathological conditions, will come from the already promising development of GnRH-secreting neurons from neuronal stem cells and induced pluripotent stem cells (iPSCs).