de Bettignies, A.S.; (2007) Wnt/Fz interactions in the developing central nervous system. Doctoral thesis , University of London.

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Abstract

Wnt signalling is central to many early developmental processes including embryonic patterning, programmed cell death and cell migration. Recent studies have implicated Wnt signalling in the formation of neuronal connections in the nervous system. Wntl a regulates synapse formation in the cerebellum by inducing presynaptic differentiation characterized by axonal remodelling and presynaptic assembly. A very similar gene, Wnt7b regulates dendritic development in hippocampal neurons, but can also trigger axonal remodelling. These different responses are due to the activation of different signalling pathways. We aim to identify the receptors triggering these processes in neurons. Intracellular signalling by Wnts is initiated by the activation of their seven transmembrane receptors Frizzled (Fz). Three known Wnt signalling pathways may be activated: the canonical, the planar cell polarity and Calcium pathways. Ten Fz receptors and 19 Wnts have been identified in the mouse genome. To begin to address what Fz receptors are used by Wnts, we examined the pattern of expression of Wnt 7a and Wnt 7b together with several Fz receptors during postnatal brain development. We found that Wnt7a,fz7, and fz3 are expressed in the postnatal and adult cerebellum. Wnt7b and fz3 are highly expressed in the postnatal hippocampus. These overlapping patterns of expression led us to investigate the ability of Wnt7a and Wnt7b to bind to the cell surface of HEK293 cells expressing the ligand-binding domain of Fz receptors. Binding of Wnt7a an -7b to Fz-3, -5, -7 and -8 was tested. Wnt7b binds Fz3 and Fz5, whilst Wnt7a binds Fz7 and Fz3. Signalling activity was then assessed by measuring TCF/LEF mediated transcription (Top-Flash assay) and by the increased levels of 6-catenin. Wnt-7a is able to activate the canonical pathway in Fz7 and Fz3/LRP6 transfected HEK293 cells. These studies highlight the idea that activation of the canonical / p-catenin pathway by Wnt7a can be mediated by Fz7 and the LRP6/Fz3 complex.

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