The unravelling of the genetic basis of the hypogonadotrophic hypogonadal disorders, including
Kallmann syndrome (KS), has led to renewed interest into the developmental biology of gonadotrophin-releasing
hormone (
GnRH) neurones and, more generally, into the molecular mechanisms of reproduction. KS is characterised by the association of
GnRH deficiency with diminished olfaction. Until recently, only two KS-associated genes were known: KAL1 and KAL2. KAL1 encodes the cell membrane and extracellular matrix-associated secreted
protein anosmin-1 which is implicated in the X-linked form of KS. Anosmin-1 shows high affinity binding to heparan sulphate (HS) and its function remains the focus of ongoing investigation, although a role in axonal guidance and neuronal migration, which are processes essential for normal
GnRH ontogeny and olfactory bulb histogenesis, has been suggested. KAL2, identified as the
fibroblast growth factor receptor 1 (FGFR1) gene, has now been recognised to be the underlying genetic defect for an autosomal dominant form of KS. The diverse signalling pathways initiated upon FGFR activation can elicit pleiotropic cellular responses depending on the cellular context. Signalling through FGFR requires HS for receptor dimerisation and
ligand binding. Current evidence supports a HS-dependent interaction between anosmin-1 and FGFR1, where anosmin-1 serves as a co-
ligand activator enhancing the signal activity, the finer details of whose mechanism remain the subject of intense investigation. Recently, mutations in the genes encoding prokineticin 2 (PK2) and prokineticin receptor 2 (PKR2) were reported in a cohort of KS patients, further reinforcing the view of KS as a multigenic trait involving divergent pathways. Here, we review the historical and current understandings of KS and discuss the latest findings from the molecular and cellular studies of the KS-associated
proteins, and describe the evidence that suggests convergence of several of these pathways during normal
GnRH and olfactory neuronal ontogeny.