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The Journal of Neuroscience, March 23, 2005, 25(12):3142-3150; doi:10.1523/JNEUROSCI.4759-04.2005

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Development/Plasticity/Repair
Disruption of Ephrin Signaling Associates with Disordered Axophilic Migration of the Gonadotropin-Releasing Hormone Neurons

John A. Gamble,¹ Delicia K. Karunadasa,¹ Jean-Rémi Pape,¹ Michael J. Skynner,¹ Martin G. Todman,¹ R. John Bicknell,¹ Jeremy P. Allen,¹ and Allan E. Herbison^1,2

¹Neurobiology Programme, The Babraham Institute, Cambridge CB2 4AT, United Kingdom, and ²Centre for Neuroendocrinology and Department of Physiology, University of Otago School of Medical Sciences, Dunedin 9001, New Zealand

Ephrin signaling is involved in repulsive and attractive interactions mediating axon guidance and cell-boundary formation in the developing nervous system. As a result of a fortuitous transgene integration event, we have identified here a potential role for EphA5 in the axophilic migration of gonadotropin-releasing hormone (GnRH) neurons from the nasal placode into the brain along ephrin-expressing vomeronasal axons. Transgene integration in the GNR23 mouse line resulted in a 26 kb deletion in chromosome 5, 67 kb 3' to Epha5. This induced a profound, region-specific upregulation of EphA5 mRNA and protein expression in the developing mouse brain. The GnRH neurons in GNR23 mice overexpressed EphA5 from embryonic day 11, whereas ephrin A3 and A5 mRNA levels in olfactory neurons were unchanged. The GnRH neurons were found to be slow in commencing their migration from the olfactory placode and also to form abnormal clusters of cells on the olfactory axons, prohibiting their migration out of the nose. As a result, adult hemizygous mice had only 40% of the normal complement of GnRH neurons in the brain, whereas homozygous mice had <15%. This resulted in infertility in adult female homozygous GNR23 mice, suggesting that some cases of human hypogonadotropic hypogonadism may result from ephrin-related mutations. These data provide evidence for a role of EphA-ephrin signaling in the axophilic migration of the GnRH neurons during embryogenesis.

Key words: GnRH; ephrin; migration; embryogenesis; transgenic; lhrh

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Received Nov 21, 2004; revised February 10, 2005; accepted February 11, 2005.

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