Fig. 8. Hh-PKA signalling regulates two steps of RGC differentiation in zebrafish. (A) Model for PKA-mediated inhibition of the cell-cycle exit of retinoblasts. PKA interacts with both the Hh and the Wnt signalling pathway. PKA inhibits Hh-mediated Gli activation. The activator form of Gli may promote the expression of p27. Another possible pathway is that PKA promotes the phosphorylation of Ser133 of CREB. This phosphorylation may activate the transcriptional activity of the ß-catenin/Tcf3 complex to elevate the expression of cyclin D1. (B) Model of Hh actions in the Drosophila compound eye and the zebrafish retina. In Drosophila, Hh is expressed in photoreceptors and acts on adjacent retinoblasts to induce the proneural gene atonal, which promotes the differentiation of photoreceptors. Thus, a single cycle of Hh activation and cell differentiation advances the neurogenic wave across the fly eye. By contrast, in zebrafish Hh signalling regulates at least two steps of RGC differentiation: the cell-cycle-exit of retinoblasts and the maturation of RGCs. Shh or Twhh acts as a short-range signal to induce the cell-cycle exit of retinoblasts and ath5 expression. ath5-positive cells located in the wave front may be a source of Hh signals. In the later stages, ath5-positive neurons differentiate into mature RGCs and express high levels of Shh/Twhh, which act on adjacent ath5-positve neurons causing them to differentiate into mature RGCs. In this model, dual cycles of Hh activation and cell differentiation cooperatively regulate the differentiation of RGCs.