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The Journal of Neuroscience, February 28, 2007, 27(9):2387-2395; doi:10.1523/JNEUROSCI.5075-06.2007

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Development/Plasticity/Repair
Neuropilins and Their Ligands Are Important in the Migration of Gonadotropin-Releasing Hormone Neurons

Anna Cariboni,^1,3 Jason Hickok,² Sonja Rakic,¹ William Andrews,¹ Roberto Maggi,³ Shelley Tischkau,² and John G. Parnavelas¹

¹Department of Anatomy and Developmental Biology, University College London, London WC1E 6BT, United Kingdom, ²Department of Veterinary Biosciences, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, and ³Department of Endocrinology, University of Milan, 20133 Milan, Italy

Correspondence should be addressed to John G. Parnavelas, Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK. Email: j.parnavelas{at}ucl.ac.uk

Gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus play an important role in reproductive function. These cells originate in the nasal compartment and migrate into the basal forebrain in association with olfactory/vomeronasal nerves in embryonic life in rodents. Here, we studied the role of neuropilins and their ligands, semaphorins, in the development of the olfactory-GnRH system. We focused on Neuropilin-2 knock-out (Npn-2^–/–) mice, because they are known to display defasciculation of olfactory nerves and reduced fertility. We found a significant decrease in the number of GnRH neurons in the hypothalamus and a marked reduction in their gonadal size. We then observed an abnormal increase of GnRH neurons in the noses of Npn-2^–/– mice, indicating that these cells failed to migrate into the forebrain. However, because neuropilins and semaphorins are involved in events of neuronal migration in the brain, we asked whether the observed reduction in GnRH neurons was directly attributable to the action of these molecules. Using fluorescence-activated cell sorting and reverse transcription-PCR on mRNA derived from embryonic green fluorescent protein (GFP)–GnRH transgenic mice, we found expression of class 3 semaphorins and their receptors (neuropilin-1/2 and plexin-A1) in GnRH neurons. Furthermore, double-immunofluorescence experiments showed that migrating GnRH neurons, as well as associated olfactory fibers, express Npn-2 in the nasal region. We then used a line of immortalized GnRH neurons (GN11 cells) that display the same expression patterns for semaphorins and their receptors as GFP–GnRH cells and found that class 3 semaphorins and vascular endothelial growth factors modulate their migratory activity. These studies provide support for the direct involvement of neuropilins and their ligands in the establishment of the GnRH neuroendocrine system.

Key words: GnRH neurons; hypothalamus; migration; neuropilin; reproduction; semaphorin

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Received July 31, 2006; revised Jan. 25, 2007; accepted Jan. 27, 2007.

Correspondence should be addressed to John G. Parnavelas, Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK. Email: j.parnavelas{at}ucl.ac.uk

This article has been cited by other articles:

				P. Giacobini, A. Messina, F. Morello, N. Ferraris, S. Corso, J. Penachioni, S. Giordano, L. Tamagnone, and A. Fasolo Semaphorin 4D regulates gonadotropin hormone-releasing hormone-1 neuronal migration through PlexinB1-Met complex J. Cell Biol., November 3, 2008; 183(3): 555 - 566. [Abstract] [Full Text] [PDF]

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