Endocrine Abstracts

Kallmann’s syndrome (KS) is proposed to result from disrupted migration of both olfactory sensory axons and hypothalamic gonadotrophin-releasing hormone (GnRH1) neurons during embryogenesis. KAL1 (encoding anosmin-1) and KAL2 (encoding the fibroblast growth factor receptor 1, FGFR1) are responsible for approximately 20% of KS cases, and in an ex vivo system it has been reported that anosmin-1 enhances FGFR1 signalling in a ligand (FGF)- and heparan sulphate-dependent manner. The zebrafish provides a very attractive system to model KS in vivo because their transparent embryos develop externally allowing all developmental stages to be visualised in real-time, and moreover, zebrafish KAL1 orthologues (Kal1a and Kal1b) have been identified. We have generated transgenic fish in which the extending olfactory axons and hypothalamic GnRH neuroblasts can be distinguished by different-coloured fluorescent proteins from the onset of their development. We have been using these fish to understand the proposed relationship between the migration of these two populations during normal development. The GnRH1 gene is not present in the zebrafish genome; however, using our pGnRH3-mCherry reporter line we have shown that mCherry positive neurons are present in the hypothalamus by 55 h post-fertilisation, and it therefore seems likely that the GnRH3 decapeptide has assumed the reproductive role of GnRH1 in the zebrafish. Moreover, using antisense oligonucleotide (morpholino) approaches, we have investigated the effects of inhibiting Kal1a and/or Kal1b, as well as FGFR1 and other components of the FGF signalling pathway. Using this approach, preliminary results have shown that loss of one or both of the KAL1 orthologues resulted in a noticeable deficiency in the number of olfactory sensory neurons projecting to the olfactory bulbs. Our ability to image axonogenesis and neuroblast migration in live embryos will further facilitate a more precise understanding of the disease mechanism.