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

Dev Neurobiol. 2008 Mar;68(4):487-503. doi: 10.1002/dneu.20594.

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cell Movement / physiology*
  • Chemokine CXCL12 / metabolism*
  • Embryo, Mammalian
  • Gonadotropin-Releasing Hormone / metabolism*
  • Immunohistochemistry
  • Lasers
  • Mice
  • Microdissection
  • Olfactory Bulb / embryology
  • Olfactory Bulb / ultrastructure
  • Olfactory Mucosa / metabolism
  • Olfactory Mucosa / ultrastructure
  • Olfactory Pathways / embryology*
  • Olfactory Pathways / ultrastructure
  • Olfactory Receptor Neurons / embryology*
  • Olfactory Receptor Neurons / metabolism
  • Olfactory Receptor Neurons / ultrastructure
  • Protein Precursors / metabolism*
  • Receptors, CXCR4 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Vomeronasal Organ / metabolism
  • Vomeronasal Organ / ultrastructure

Substances

  • CXCR4 protein, mouse
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Protein Precursors
  • Receptors, CXCR4
  • progonadoliberin I
  • Gonadotropin-Releasing Hormone