Disruption of ephrin signaling associates with disordered axophilic migration of the gonadotropin-releasing hormone neurons

被引:46
作者
Gamble, JA
Karunadasa, DK
Pape, JR
Skynner, MJ
Todman, MG
Bicknell, RJ
Allen, JP
Herbison, AE
机构
[1] Univ Otago, Sch Med Sci, Ctr Neuroendocrinol, Dunedin 9001, New Zealand
[2] Univ Otago, Sch Med Sci, Dept Physiol, Dunedin 9001, New Zealand
[3] Babraham Inst, Neurobiol Programme, Cambridge CB2 4AT, England
关键词
GnRH; ephrin; migration; embryogenesis; transgenic; lhrh;
D O I
10.1523/JNEUROSCI.4759-04.2005
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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, similar to 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 similar to 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.
引用
收藏
页码:3142 / 3150
页数:9
相关论文
共 37 条
[1]   Topographic mapping from the retina to the midbrain is controlled by relative but not absolute levels of EphA receptor signaling [J].
Brown, A ;
Yates, PA ;
Burrola, P ;
Ortuño, D ;
Vaidya, A ;
Jessell, TM ;
Pfaff, SL ;
O'Leary, DDM ;
Lemke, G .
CELL, 2000, 102 (01) :77-88
[2]   Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome [J].
Dodé, C ;
Levilliers, J ;
Dupont, JM ;
De Paepe, A ;
Le Dû, N ;
Soussi-Yanicostas, N ;
Coimbra, RS ;
Delmaghani, S ;
Compain-Nouaille, S ;
Baverel, F ;
Pêcheux, C ;
Le Tessier, D ;
Cruaud, C ;
Delpech, M ;
Speleman, F ;
Vermeulen, S ;
Amalfitano, A ;
Bachelot, Y ;
Bouchard, P ;
Cabrol, S ;
Carel, JC ;
Delemarre-van de Waal, H ;
Goulet-Salmon, B ;
Kottler, ML ;
Richard, O ;
Sanchez-Franco, F ;
Saura, R ;
Young, J ;
Petit, C ;
Hardelin, JP .
NATURE GENETICS, 2003, 33 (04) :463-465
[3]   Loss-of-function analysis of EphA receptors in retinotectal mapping [J].
Feldheim, DA ;
Nakamoto, M ;
Osterfield, M ;
Gale, NW ;
DeChiara, TM ;
Rohatgi, R ;
Yancopoulos, GD ;
Flanagan, JG .
JOURNAL OF NEUROSCIENCE, 2004, 24 (10) :2542-2550
[4]   The ephrins and Eph receptors in neural development [J].
Flanagan, JG ;
Vanderhaeghen, P .
ANNUAL REVIEW OF NEUROSCIENCE, 1998, 21 :309-345
[5]  
Franklin K. B. J., 2013, PAXINOS FRANKLINS MO
[6]   Ephrins and their Eph receptors:: multitalented directors of embryonic development [J].
Frisén, J ;
Holmberg, J ;
Barbacid, M .
EMBO JOURNAL, 1999, 18 (19) :5159-5165
[7]   Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis [J].
Gale, NW ;
Holland, SJ ;
Valenzuela, DM ;
Flenniken, A ;
Pan, L ;
Ryan, TE ;
Henkemeyer, M ;
Strebhardt, K ;
Hirai, H ;
Wilkinson, DG ;
Pawson, T ;
Davis, S ;
Yancopoulos, GD .
NEURON, 1996, 17 (01) :9-19
[8]   Retinal axon response to ephrin-as shows a graded, concentration-dependent transition from growth promotion to inhibition [J].
Hansen, MJ ;
Dallal, GE ;
Flanagan, JG .
NEURON, 2004, 42 (05) :717-730
[9]   Kallmann syndrome: towards molecular pathogenesis [J].
Hardelin, JP .
MOLECULAR AND CELLULAR ENDOCRINOLOGY, 2001, 179 (1-2) :75-81
[10]   Regulated cleavage of a contact-mediated axon repellent [J].
Hattori, M ;
Osterfield, M ;
Flanagan, JG .
SCIENCE, 2000, 289 (5483) :1360-1365