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Title: Role of fibroblast growth factor signalling in development and function of the choroid plexus
Author: Swetloff, Adam Patrick
ISNI:       0000 0001 3494 0373
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2005
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This thesis investigated how fibroblast growth factor (FGF) signalling affects the development and function of the choroid plexus epithelium (CPe) that is normally involved in the secretion and homeostasis of the cerebrospinal fluid. In doing so, it aimed to understand whether the constitutive activation of FGF receptors underlying several cases of syndromic craniosynostosis may affect the development and function of the CPe, and thus be in part responsible for the raised intra-cranial pressure (ICP) and hydrocephalus observed in some of these patients. I showed that the genes E2F5, FoxJ1 and p73 involved in the maturation of the CPe and whose knockout cause hydrocephalus were expressed in the developing mouse CPe and the expression was conserved in human embryonic CPe. I used two cell culture models to test the effect of FGF2 on the function of CPe cells: 1) primary mouse embryonic CPe cells. Dissociated cells were seeded in a tridimensional basement membrane matrix (Matrigel) where, following aggregation, they formed fluid-filled hollow vesicles; 2) adult rat CPe cell line (TRCSFB-2) transformed with tsSV40 T-antigen grown as a monolayer. I extended the analysis of the phenotype of the cells in these culture models by showing they expressed E2F5, FoxJ1 and p73, as well as the CPe marker TTR and the tight junction associated protein ZO-1. I characterized the sequence of events and cellular mechanism leading to CPe vesicle formation in Matrigel using time-lapse microscopy, and showed that the vesicles actively secreted fluid by using secretion inhibitors. I also demonstrated that FGF2 increased the size of the vesicles by increasing cell recruitment but did not affect cell proliferation or fluid secretion. In fact, FGF2 appeared to inhibit secretion. In TRCSFB-2 cells I found that FGF2 decreased the expression of E2F5 and FoxJ1 transcripts, and only a low dose of FGF2 strongly increased cell proliferation. Finally, I investigated in a mouse model of Apert-Pfeiffer syndromes whether the knockout of the FgfR2IIIc isoform affected the ventricular size. I did not observe any abnormalities in the CPe of these animals nor a ventricular enlargement. However, a higher number of neuronal cells seemed to be generated in the cortex of these mutants. Overall I have provided novel information on the behaviour of CPe cells and the effect of FGF2 on these cells. The future challenge will be to establish whether abnormal FGF-signalling affects fluid secretion and cell proliferation in the context of syndromic craniosynostosis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available