Reid, Sarah Lucy; (2002) Fibroblast growth factor signalling in the development and functions of the choroid plexus. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The choroid plexuses (CPs) are secretory organs that lie within the brain ventricles. Mature CPs produce cerebrospinal fluid (CSF) which surrounds the central nervous system (CNS). During embryogenesis, prior to terminal differentiation of neurons and glia, CPs are morphologically distinct and have secretory capacity, suggesting that CPs may influence the extracellular environment of the developing CNS. Although the roles of fibroblast growth factors (FGFs) as morphogenic and mitogenic signals during CNS development are well characterised, they have not been addressed in embryonic CPs. In this study, I investigated the FGF receptor (FGFR) family in relation to CP development and function. I found that several FGFRs are differentially expressed in the CPs during murine development. This finding was important because many individuals with the human disorder, syndromic craniosynostosis (SCS), have constitutively active FGFRs, and frequently suffer from raised intracranial pressure. This led to the hypothesis that increased FGFR signalling alters the function of the CPs. In order to elucidate the functional role of FGF signalling in the embryonic CP, I used several approaches. Firstly, I cultured CP epithelial cells (CPe) in Matrigel, and demonstrated that CPe in this matrix formed hollow vesicles, maintained their ultrastructural characteristics, and had secretory activity. I found that the CPe marker, transthyretin, was expressed in culture. Treatment of CPe with FGF2 significantly increased vesicle diameter, but did not seem to alter secretion, indicating that the FGF2 effect was on vesicle formation. Secondly, I cultured CPe monolayers, and established that at least one effect of FGF2 was to stimulate CPe cell division. An analysis of proteins in CSF of children with SCS showed no significant change in the concentration of transthyretin secreted by the CPs. These data indicate that FGF signalling is involved in CP development, and that FGFs may function to stimulate CP proliferation, rather than affecting CSF constituents or CP secretion rates during embryonic development.

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