Leukemia inhibitory factor promotes the chemomigration of immature GnRH neurons

Leukemia inhibitory factor (LIF), a pleiotropic cytokine of the interleukine-6 superfamily, is involved in several functions including the control of reproduction at the embrionic-endometrial interface and the regulation of energy homeostasis. LIF activates a cell-surface receptor complex (LIF-Rs) composed of one ligand-specific low affinity LIF receptor β (LIFRβ) subunit and the gp130 subunit. Since little is known about the involvement of LIF in the modulation of the neuroendocrine circuitry governing the reproductive function and, specifically, of the migration of gonadotrophin releasing-hormone (GnRH) neurons from the olfactory placode to the hypothalamus, we tested whether LIF could exert a chemoattractant or chemotropic action on GN11 immortalized cells, an in vitro model of immature and migratory GnRH neurons. GN11 cells were found to express LIFRβ and gp130 genes and proteins. Exposure to 100 ng/mL LIF activated the Janus kinases (Jak)-signal transducer and activator of transcription 3 (STAT3), the mitogen-activated protein kinase (MAPK)-extracellular regulated kinase 1/2 (ERK1/2) and the phosphatidylinositol 3-kinase (PI3-K)-Akt pathways. The selective inhibition of Jaks, MEK, and PI3-K indicated that in GN11 cells the three signalling pathways were activated independently and that Jak2 is not the main Jak involved in LIF signalling. LIF stimulated chemotaxis at a concentration-dependent manner, with a plateau at 100 ng/mL after both 3 and 20 h of incubation. A 3-h treatment with 100 ng/mL LIF also induced chemokinesis. All the three signalling pathways activated by LIF in GN11 cells were independently involved in LIF-induced cell migration. In conclusions, the present results indicate that LIF promotes the chemomigration of immature GnRH neurons, and suggest that LIF may modulate the development of the reproductive axis by directly influencing the migration of GnRH neurons to the hypothalamus.