Disruption of ephrin signaling associates with disordered axophilic migration of the gonadotropin-releasing hormone neurons.
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, approximately 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.
Gamble
John A
JA
Neurobiology Programme, The Babraham Institute, Cambridge CB2 4AT, United Kingdom.
Karunadasa
Delicia K
DK
Pape
Jean-Rémi
JR
Skynner
Michael J
MJ
Todman
Martin G
MG
Bicknell
R John
RJ
Allen
Jeremy P
JP
Herbison
Allan E
AE
D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002465:Cell Movement / Q000502:physiology*; D002874:Chromosome Mapping / Q000379:methods; D004622:Embryo, Mammalian; D036342:Ephrins / Q000145:classification / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D015698:Genomic Library; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D036123:Receptor, EphA5 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012794:Sialic Acids / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D036342:Ephrins; D039842:Neural Cell Adhesion Molecule L1; D012333:RNA, Messenger; D012794:Sialic Acids; C103469:polysialyl neural cell adhesion molecule; D007987:Gonadotropin-Releasing Hormone; D036123:Receptor, EphA5