Regan, JC; (2008) FGF-signalling and the development of CNS asymmetry in zebrafish. Doctoral thesis , UCL (University College London).

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Abstract

Neuroanatomical and functional asymmetries are a widespread, probably universal, feature of the vertebrate nervous system. Although brain asymmetry is a fundamental characteristic of the CNS, how it is established is not known. The epithalamus is a subdivision of the diencephalic region of the forebrain and structural asymmetries in this region are widespread among vertebrates. The epithalamus of the zebrafish shows differences between the left and right sides in terms of neuronal organization, connectivity and gene expression and has become a focus for the study of establishment and elaboration of brain asymmetry. Unilateral Nodal expression in the dorsal diencephalon of zebrafish embryos is required for correct lateralisation of the epithalamus. However, in embryos lacking Nodal signalling asymmetries still develop, but their sidedness is randomised among siblings. This suggests that Nodal is not required for asymmetric development per se and that other signals are responsible for generating asymmetry. In order to uncover signalling pathways required to break symmetry in the brain, we aimed to identify mutant lines that do not show elaboration of CNS asymmetries. In this thesis I describe the phenotype of the/g/8 mutant, acerebellar (ace), which develops a symmetric epithalamus. The parapineal does not migrate and remains at the midline and later epithalamic asymmetries do not develop. However, unilateral Nodal signalling in the brain and body axis are largely unaffected in ace mutants. Fgf8 is expressed bilaterally in the epithalamus in wild type embryos, as are some Fgf-responsive genes. Additionally, several Fgf-pathway genes are expressed specifically in the migrating parapineal. Using a modified Fgf8 micro-bead implantation technique, I am able to rescue the lateralised migration of the parapineal in ace mutants. In situations of unbiased Nodal signalling, exogenous Fgf8 can impose laterality on the epithalamus. In summary, these studies demonstrate that Fgf8 can break neuroanatomical symmetry in the epithalamus through the regulation of the bi-stable left- or right-sided migration of the parapineal. I present a mechanism whereby the combined action of Nodal and Fgf signals ensures the establishment of neuroanatomical asymmetries with consistent laterality.

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