INTRODUCTION Kallmann syndrome (KS) is characterized by hypogonadotropic hypogonadism and inability to smell (anosmia), owing to impaired targeting and migration of olfactory axons and gonadotropin-releasing hormone (GnRH)-secreting neurons

Kallmann syndrome (KS) is characterized by hypogonadotropic hypogonadism and inability to smell (anosmia), owing to impaired targeting and migration of olfactory axons and gonadotropin-releasing hormone (GnRH)-secreting neurons (Kallmann, 1944). During normal development, olfactory neurons project their axons through the cribriform plate and the meningeal tissue and enter the olfactory bulb. GnRH neurons migrate along the pathway of the olfactory nerve and across the olfactory bulb to eventually reach the hypothalamus (Schwanzel-Fukuda and Pfaff, 1989; Wray et al., 1989). In KS, these migrations appear defective, and both olfactory axons and GnRH neurons are found bundled within the meninges above the cribriform plate (Schwanzel-Fukuda et al., 1989). In addition, individuals with KS have severe hypoplasia or aplasia of olfactory bulbs and tracts, and, less commonly, unilateral renal aplasia and defects in closure of the lip and of the palate, which may reflect alterations in cell migration (Colquhoun-Kerr et al., 1999; Hermanussen and Sippell, 1985; Wegenke et al., 1975). Guidance defects of specific axonal tracts have been postulated, as several individuals with KS display other neurological symptoms, such as mirror movements, sensorineural deafness (White et al., 1983), eye-movement abnormalities, cerebellar ataxia and gaze-evoked horizontal nystagmus (Schwankhaus et al., 1989; Sunohara et al., 1986). The gene responsible for the X-linked form of the disease (KAL-1) (Franco et al., 1991; Legouis et al., 1991) encodes an extracellular matrix protein, containing a putative protease inhibitor domain (WAP domain) followed by fibronectin type III (FNIII) repeats. KAL is expressed in the olfactory bulb, the central target of olfactory axons, at the time when innervation begins (Legouis et al., 1993; Rugarli et al., 1993). One study showed that KAL displays adhesive properties for a variety of neuronal and non-neuronal cell types, and modulates neurite outgrowth of cerebellar neurons in vitro (Soussi-Yanicostas et al., 1998). It has been suggested that KAL is involved in terminal steps of olfactory axon guidance to the bulb and that olfactory bulb hypoplasia/aplasia in KS is secondary to lack of innervation. Similarly, GnRH migration impairment has been 1283 Development 129, 1283-1294 (2002) Printed in Great Britain © The Company of Biologists Limited 2002 DEV14516