sense of smell mediates communication with the external environment through the recognition of chemical cues. functional VNO in humans has been recently documented but whether humans use this system to process and to respond to chemical signals emitted by other members of the species remains controversial (Dulac and Axel 1995; Berliner et al. 1996; Herrada and Dulac 1997; Monti-Bloch et al. 1998; Stern and McClintock 1998). However regardless of the role of the VNO as a sensory organ in our species it is now clear from the study of the X-linked disorder Kallmann syndrome (MIM 308700 MIM 147950 and MIM 244200) that development of the olfactory and vomeronasal system is required for normal sexual maturation. Here I review studies by neurobiologists particularly those BTZ043 working in the developing chick as well as the human genetic analysis that has brought this surprising connection to light. Development of the Olfactory System The olfactory system is unique in several respects and has received a great deal of attention from developmental neurobiologists in recent years. Olfactory sensory neurons continue to be regenerated from stem cells in the neuroepithelium BTZ043 during adult life-a rare example of persistent neurogenesis in mammals (Monti Graziadei and Graziadei 1979). Thus the mechanisms that govern the precise pattern of projections of olfactory axons to the forebrain must operate throughout a lifetime. Furthermore projections of olfactory neurons occur in a stereotyped manner: a series of elegant experiments demonstrated that the olfactory neurons that express a given receptor for some specific odorant all converge to a small number of glomeruli in the bulb despite being scattered apparently randomly within one of four areas in the olfactory epithelium (Mombaerts et al. 1996). Guidance cues therefore must be present in the olfactory epithelium and in the olfactory bulb to mediate migration to the forebrain recognition and invasion of the target and ultimately the establishment of a refined spatial map (for review see Lin and Ngai 1999). Beside giving rise to the primary olfactory sensory neurons the olfactory epithelium generates a population of migrating neuroblasts which ultimately reside in IL6ST the hypothalamus (Schwanzel-Fukuda and Pfaff 1989; Wray et al. 1989). In the adult these neurons secrete gonadotropin-releasing hormone (GnRH) the key brain-peptide hormone in vertebrates that controls the synthesis and BTZ043 the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gonadotropes. In all vertebrate species in which the matter has been examined GnRH neurons originate in the olfactory placode and migrate during embryonic development into the forebrain along branches of the vomeronasal nerve (Schwanzel-Fukuda and Pfaff 1990). Both the amino-acid sequence of GnRH and the developmental origin of the neurons producing this peptide have been essentially conserved throughout 500 million years of vertebrate evolution. Although extensive neuronal migration characterizes development of the entire CNS GnRH neurons are extraordinary because they are the only CNS neurons that are born peripherally and so require a mechanism of entry into the developing brain. Very little is known about the factors that modulate the migration of GnRH neurons from the olfactory placode to the hypothalamus. It is still a matter of debate whether specific cues are required to promote GnRH migration to the brain or whether this migration is only dependent on the presence of successful connections between the brain and the olfactory nerves. To be sure GnRH migration has been shown to occur preferentially along axons since in the absence of the route provided by the vomeronasal nerve these neurons are able to migrate on the ophthalmic branch of the trigeminal nerve BTZ043 (Murakami et al. 1998). Cell-adhesion molecules (CAMs) expressed on the vomeronasal axons likely play an important role in promoting GnRH migration (Norgren and Brackenbury 1993). Indeed GnRH neurons show a strong preference for migrating in association with axonal bundles that express a polysialic acid-rich (PSA) form of NCAM and enzymatic removal of PSA strongly inhibits GnRH migration (Yoshida et al. 1999). Surprisingly however recent studies on NCAM and NCAM-180 knock-out mice showed that migration of GnRH neurons was not overtly affected although in NCAM-180 mutants there was a tendency for PSA to be associated with NCAM-140 and for GnRH neurons to migrate along.