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The Journal of Neuroscience, May 19, 2004, 24(20):4737-4748; doi:10.1523/JNEUROSCI.0649-04.2004

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Development/Plasticity/Repair
Cholecystokinin Modulates Migration of Gonadotropin-Releasing Hormone-1 Neurons

Paolo Giacobini,^1,2 Alan S. Kopin,³ Philip M. Beart,^4,5 Linda D. Mercer,^4,5 Aldo Fasolo,² and Susan Wray¹

¹Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-4156, ²Laboratory of Neurobiology, Department of Human and Animal Biology, University of Turin, Turin, Italy 10123, ³Department of Medicine and Molecular Pharmacology Research Center, Tufts–New England Medical Center, Boston, Massachusetts 02111, ⁴Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia, and ⁵Howard Florey Institute, University of Melbourne, Parkville, Victoria 3010, Australia

Expression of the brain–gut peptide cholecystokinin (CCK) in the developing olfactory–gonadotropin-releasing hormone-1 (GnRH-1) neuroendocrine systems was characterized, and the function of CCK in these systems was analyzed both in vivo and in vitro. We present novel data demonstrating that CCK transcript and protein are expressed in sensory cells in the developing olfactory epithelium and vomeronasal organ, with both ligand and receptors (CCK-1R and CCK-2R) found on olfactory axons throughout prenatal development. In addition, migrating GnRH-1 neurons in nasal regions express CCK-1R but not CCK-2R receptors. The role of CCK in olfactory–GnRH-1 system development was evaluated using nasal explants, after assessing that the in vivo expression of both CCK and CCK receptors was mimicked in this in vitro model. Exogenous application of CCK (10-⁷ M) reduced both olfactory axon outgrowth and migration of GnRH-1 cells. This inhibition was mediated by CCK-1R receptors. Moreover, CCK-1R but not CCK-2R antagonism caused a shift in the location of GnRH-1 neurons, increasing the distance that the cells migrated. GnRH-1 neuronal migration in mice carrying a genetic deletion of either CCK-1R or CCK-2R receptor genes was also analyzed. At embryonic day 14.5, the total number of GnRH-1 cells was identical in wild-type and mutant mice; however, the number of GnRH-1 neurons within forebrain was significantly greater in CCK-1R^–/– embryos, consistent with an accelerated migratory process. These results indicate that CCK provides an inhibitory influence on GnRH-1 neuronal migration, contributing to the appropriate entrance of these neuroendocrine cells into the brain, and thus represent the first report of a developmental role for CCK.

Key words: GnRH-1; CCK; CCK receptors; migration; olfactory system; development

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Received Jan 9, 2004; revised March 29, 2004; accepted April 1, 2004.

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