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.

SDF and GABA interact to regulate axophilic migration of GnRH neurons

“…A gradient of SDF-1 mRNA expression along the migratory path of GnRH neurons suggested that SDF-1 might act as a guidance cue (Schwarting et al, 2006). However, SDF-1 was not required for directional movement of GnRH neurons in nasal explants, although blocking SDF-1 signaling reduced movement rates (Toba et al, 2008). These results suggested that the primary function of SDF-1 signaling was linked to neuronal movement per se rather than directional guidance.…”

“…Both in vivo and in nasal explants, SDF-1 producing cells are present, CXCR4 (a SDF-1 receptor) is expressed by GnRH neurons and absence or chronic inhibition of this system decreased GnRH cell movement (Schwarting et al, 2006;Toba et al, 2008). Thus, SDF-1 could be facilitating movement of GnRH neurons in the absence of GABAergic signals.…”

“…Next, the speed of neurons in explants with MNC was recorded pre-and post-application of the CXCR4 receptor antagonist AMD3100 (25 mg/ml) (Toba et al, 2008). AMD3100 significantly decreased (212% , Table 3; Fig.…”

“…In CXCR4 knockout mice, most GnRH neurons fail to migrate away from the vomeronasal organ (Schwarting et al, 2006;Toba et al, 2008). A gradient of SDF-1 mRNA expression along the migratory path of GnRH neurons suggested that SDF-1 might act as a guidance cue (Schwarting et al, 2006).…”

“…In patients with Kallmann syndrome, malformation of the olfactory system and failure of GnRH neurons to migrate into the brain results in anosmia and delayed or absent pubertal maturation (hypogonadotropic hypogonadism) (Iovane et al, 2004). Among the numerous molecules involved in GnRH neuronal migration, GABA (Fueshko et al, 1998b;Wray et al, 1996;Bless et al, 2000), and SDF-1 (Schwarting et al, 2006;Toba et al, 2008) are potent regulators within the nasal compartment.…”