CXCR4/SDF-1 system modulates development of GnRH-1 neurons and the olfactory system

Abstract

Stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 influence neuronal migration and have been identified in nasal regions. Gonadotropin releasing hormone-1 (GnRH-1) neurons migrate from nasal regions into the developing forebrain, where postnatally they control reproduction. This study examined the role of SDF-1/CXCR4 in development of the GnRH-1/olfactory systems. Migrating GnRH-1 neurons were CXCR4 immunopositive as were the fibers along which they migrate. SDF-1 transcripts were detected in olfactory epithelium and vomeronasal organ, while SDF-1 immunoreactivity highlighted the GnRH-1 migratory pathway. CXCR4-deficient mice showed a decrease in GnRH-1 cells at the nasal forebrain junction and in brain, but the overall migratory pathway remained intact, no ectopic GnRH-1 cells were detected and olfactory axons reached the olfactory bulb. To further characterize the influence of SDF-1/CXCR4 in the GnRH-1 system, nasal explants were used. CXCR4 expression in vitro was similar to that in vivo. SDF-1 was detected in a dorsal midline cell cluster as well as in migrating GnRH-1 cells. Treatment of explants with bicyclam AMD3100, a CXCR4 antagonist, attenuated GnRH-1 neuronal migration and sensory axon outgrowth. Moreover, the number of GnRH-1 neurons in the explant periphery was reduced. The effects were blocked by coincubation with SDF-1. Removal of midline SDF-1 cells did not alter directional outgrowth of olfactory axons. These results indicate that SDF-1/CXCR4 signaling in not necessary for olfactory axon guidance but rather influences sensory axon extension and GnRH-1 neuronal migration, and maintains GnRH-1 neuronal expression as the cells move away from nasal pit regions.