Cadman, S.M.; (2011) Modelling Kallmann syndrome in the zebrafish. Doctoral thesis, UCL (University College London).
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Kallmann syndrome (KS) is a human genetic disorder characterised by delayed/absent pubertal development, associated with lack of olfaction. KS is proposed to result from disrupted migration and targeting of olfactory sensory axons and hypothalamic gonadotrophin releasing hormone (GnRH1) neurons during early embryogenesis. Mutations in anosmin-1 (KAL1), fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor 8 (FGF8) are responsible for some cases of KS. Previously, in ex vivo human GnRH neuroblast culture, anosmin-1 was shown to enhance FGFR1 signalling in an FGF-dependent manner. Here, using a zebrafish in vivo system, the biological functions of anosmin-1- and FGF-mediated signalling during olfactory and GnRH system development have been investigated. Characterisation of the zebrafish GnRH system, and the role of olfactory axonogenesis in its development, was aided by the generation of a transgenic reporter line: pGnRH3:mCherry. Two notable mCherry populations were visualised by 36 hours post-fertilisation (hpf): the well-characterised terminal nerve cells, and an early, hitherto unreported, hypothalamic cluster of cells. Antisense morpholino approaches were used to demonstrate that knocking down both Kal1a and Kal1b genes, the two zebrafish KAL1 orthologues, caused noticeable deficiency in the number of olfactory sensory neurons accurately projecting to the olfactory bulbs, concomitant with disruption in the terminal nerve GnRH cells and presence of fewer presumptive hypothalamic GnRH cells by 36hpf. Moreover, there was a notable failure in formation of one or both of the two forebrain commissures in these morphants. In parallel experiments, knocking down one of the two FGF8 orthologues, Fgf8a, or specific temporal pharmacological inhibition of FGFR signalling at 14-22hpf, resulted in similar phenotypes by 36hpf. Interestingly, co-injection of Kal1a/Kal1b and Fgf8a morpholinos at concentrations which would give no phenotype individually was able to replicate the commissural mutant phenotype. Combined, these data strongly suggest that Kal1a/Kal1b may act via the Fgf8a pathway in vivo.
|Title:||Modelling Kallmann syndrome in the zebrafish|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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