Figure 10.

Schematic for interactions between Wnt/ bcat and FGF signaling during midbrain development (A). Secreted Wnt proteins bind frizzled (frz) and lrp5/6 cell membrane receptors complexed with dishevelled (dvl). This results in the inhibition of the ubiquitination (Ub) and subsequent degradation of bcat by the destruction complex (DC, purple box), incorporating Axin, APC and GSK-3 proteins. Free bcat concentration then rises and bcat can translocate to the nucleus to activate gene expression by binding TCF or LEF transcription factors. Inhibition of GSK-3 by BIO results in decreased bcat protein degradation. In contrast, inhibition of Tankyrase enzyme by IWR-1 prevents ubiquitination of Axin proteins and hence increased activity of the DC. A working model for Wnt-FGF interactions at the isthmus and in the midbrain during stages when MTN neurons form (B). Wnt and FGF signaling co-regulate each others activity in GSK-3 dependent and independent manners. Wnt inhibits GSK-3 activity leading to elevated bcat activity. Spry4 expression is increased in response to bcat and FGF activity (FgfR) and acts to inhibit FgfR receptors. GSK-3 is also required for FgfR activity and acts independently of bcat activity (green arrow). FGF signaling across the midbrain represses neurogenesis through activation of her5; as the her5 expression retracts posteriorly Wnt signaling acts to promote neuronal differentiation.