Endocrine Abstracts

Recent investigations into the pathogenesis of Kallmann's syndrome (KS) have pointed to the importance of anosmin-1 and FGFR1 (fibroblast growth factor receptor-1), the gene products for the X-linked and an autosomal dominant form of KS respectively, in olfactory, GnRH-1 neuronal systems and kidney ontogeny. Disturbed anosmin-1/FGFR1 pathways lead to partial or complete failure of OB (olfactory bulb) development and arrest of GnRH-1 neuronal migration, explaining the predominant phenotypic abnormalities of anosmia and hypogonadotrophic hypogonadism.

Previous studies have described the spatiotemporal distribution of anosmin-1 in the developing nervous system. In the present study, immunohistochemical techniques and brightfield and confocal imaging were used to investigate the spatiotemporal distribution of both GnRH-1 neuronal, anosmin-1 and FRGR1 in the developing human embryo and foetus (from 4 weeks, CS13, to 10-12 weeks, F3) employing antibodies raised against the GnRH decapeptide, the recombinant human anosmin-1 protein and a recombinant human FGFR1 protein. This descriptive analysis has provided important insights into pathogenetic pathways for KS and its pleiotrophic manifestations. Anosmin-1 is expressed at week 4.5 in the olfactory placode where FGFR1 and GnRH-1 expressing cells are also present. Subsequently, at week 6, anosmin-1 is not present in this nasal region but FGFR1 is present in the presumptive olfactory bulb. At this stage, GnRH-1 cells have already reached and crossed the nasal mesenchyme and rostral forebrain and arrived at the ventral hypothalamus before the OB becomes distinct. These results suggest that anosmin-1 and FGFR1 cells and the GnRH-1 system seem to be expressed earlier than previously described; moreover, two different developmental events such as OB morphogenesis and GnRH-1 migration seem to be independently controlled by the affected genes in KS.