4709 Introduction A small number of cells known as the gonadotropin-releasing hormone (GnRH) neurons are scattered in the basal forebrain from the medial septal/preoptic region to the posterior hypothalamus. They form the final pathway for the central regulation of fertility by projecting to the median eminence where they secrete the decapeptide GnRH into the pituitary portal vessels to induce the release of gonadotropins from the pituitary gland into the general circulation (Merchenthaler et al., 1984; Barry et al., 1985). GnRH neurons originate in the nasal compartment at the level of the medial olfactory placode where they are identified by the production of GnRH mRNA or the peptide early in embryonic life (E10-11 in mouse; E12-13 in rat) (Schwanzel- Fukuda and Pfaff, 1989; Wray et al., 1989a; Wray et al., 1998b; Tobet et al., 2001). They migrate in association with olfactory/vomeronasal nerves (VNN) until they pass the cribriform plate. The fascicles of VNN split at this level, with the majority entering the main and accessory olfactory bulbs; the remaining axons, the so-called caudal VNN (cVNN), take a caudal and ventral turn and enter the basal forebrain (Schwarting et al., 2004). These pioneer axons can be labelled with the intermediate filament marker peripherin (Wray et al., 1994). Migrating GnRH neurons follow the cVNN into the basal forebrain where they detach from the guiding fibres and find their positions in the hypothalamic region by the time of birth in rodents. Only a small number of these neurons proceeds dorsally and enter the cerebral cortex (Yoshida et al., 1995). In the human, failure of GnRH neurons to migrate normally results in reproductive dysfunction and delayed or absent pubertal maturation. Kallmann’s syndrome (KS) is a genetic developmental disorder characterized by anosmia and hypogonadotropic hypogonadism (Seminara et al., 1998). In the X-linked form of the disease, the VNN and GnRH neurons fail to cross the cribriform plate and remain clustered in this area (Schwanzel-Fukuda et al., 1989). What are the molecular mechanisms that guide GnRH neurons during their long and tortuous journey from the nasal compartment to the forebrain? A number of molecules have been shown to affect their migration (reviewed by Wray, 2001; MacColl et al., 2002; Pimpinelli and Maggi, 2004; Wierman et al., 2004). Amongst them are: adhesion molecules (NCAM and its polysialylated form PSA-NCAM, peripherin, TAG-1 and nasal embryonic LHRH factor), secreted molecules (GABA, netrin-1, HGF), the transcription factor Ebf2 (Corradi et al., 2003), and the gene product responsible for the X-linked KS, anosmin-1 (Cariboni et al., 2004). Most of these molecules affect the migration of GnRH neurons indirectly by altering the underlying migratory pathway and nearly all appear to act at the early stages of their migration within the nasal compartment. The cues that instruct GnRH neurons to avoid Gonadotropin-releasing hormone (GnRH) neurons, a small number of cells scattered in the hypothalamic region of the basal forebrain, play an important role in reproductive function. These cells originate in the olfactory placode and migrate into the basal forebrain in late embryonic life. Here, we show that reelin, which is expressed along the route of the migrating cells, has an inhibitory role in guiding GnRH neurons to the basal forebrain. Only a small (approximately 5%) subpopulation of these neurons expresses one of the reelin receptors (ApoER2/Lrp8), and all GnRH neurons appear to lack the intracellular adaptor protein Dab1, suggesting that the function of reelin is not mediated by the conventional signal transduction pathway. The importance of reelin in the establishment of GnRH neurons in the hypothalamus was confirmed by our finding that the brains of developing and adult reeler mice of both sexes contained a markedly reduced number of these neuroendocrine neurons. Furthermore, the testes of adult males showed dilation of seminiferous tubules and reduction in their density when compared with controls. Mutants lacking the reelin receptors ApoER2 and Vldlr, and scrambler mice lacking Dab1, showed a normal complement of GnRH neurons in the hypothalamus, confirming that the effect of reelin in their migration is independent of Dab1. Key words: GnRH neurons, Migration, Reelin Summary Reelin provides an inhibitory signal in the migration of gonadotropin-releasing hormone neurons Anna Cariboni 1,2 , Sonja Rakic 1 , Anastasia Liapi 1 , Roberto Maggi 2 , Andre Goffinet 3 and John G. Parnavelas 1, * 1 Department of Anatomy and Developmental Biology, University College London, London WC1E 6BT, UK 2 Department of Endocrinology, Centre of Excellence on Neurodegenerative Diseases, University of Milan, 20133 Milan, Italy 3 Developmental Neurobiology Unit, University of Louvain Medical School, B1200 Brussels, Belgium *Author for correspondence (e-mail: j.parnavelas@ucl.ac.uk) Accepted 09 August 2005 Development 132, 4709-4718 Published by The Company of Biologists 2005 doi:10.1242/dev.02033 Research article Development