Endocrine Abstracts (2004) 7 S21

GnRH neuronal Ontogeny - lessons from the investigation of Kallmann's Syndrome

PMG Bouloux, Y Hu, S Kim & D Martinez Gonzalez

Unit of Neuroendocrinology, Royal Free Campus, RFUCMS, Pond Street, Hampstead, London, UK.

The defining features of Kallmann's syndrome (KS) are isolated hypogonadotrophic hypogonadism (IHH) and anosmia, the consequences of a GnRH neuronal migratory defect and olfactory bulb agenesis respectively. Additional features in X-linked Kallmann's syndrome (XKI), include unilateral renal agenesis and bimanual synkinesis respectively. XKI results from mutations of KALIG 1, on Xp22.3. The encoded protein anosmin-1, is a hexamodular secreted cell membrane associated extracellular matrix protein comprising a cysteine rich N-terminus, a WAP type domain followed by four consecutive fibronectin type III domains. Anosmin-1 is expressed in the developing olfactory bulb, but also in the forebrain, the neuroretina (amacrine cells), developing spinal cord (sulcus limitans) and metanephric blastema. There is considerable interspecies conservation of anosmin-1, with orthologues in zebrafish, chicken, quail, C Elegans and Drosophila Melanogaster (Dm) where anosmin-1 is expressed within the central projections of the antennal system. Anosmin-1 , particularly its first fibronectin module, is strongly associated with cell membrane and extracellular matrix heparan sulphate (HS) proteoglycans, with which it has < 10 nM affinity.The importance of this interaction in underlined by the observation that absence of heparan-6-0-sulphotransferase in C Elegans virtually abolishes CeKal-1 overexpression-induced phenotype. In vitro studies support a role of anosmin-1 in axonal branching, and anosmin-1 induces axon outgrowth from human GnRH producing FNCB-4 primary cell cultures of olfactory placodal origin. Anosmin-1 may interact with urokinase plasminogen activator (UPA) within the developing bulb, and has been shown to stimulate proliferation of prostatic carcinoma (PC-3) cells. In-vitro studies also show that it modulates UPA's amidolytic activity. Recently, FGFR1 receptor mutations have been shown to be associated with the autosomal dominant form of KS , and it is has been proposed that anosmin-1 may interact with the FGFR1-FGF2-HS complex to modulate signal transduction.

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