The development of the CNS depends on regionally-specific progenitors acquiring and maintaining neural potential. But what are the signals that control this process? Reporting in Neuron, Vetter and colleagues present compelling evidence that Frizzled 5 (Fz5) regulates the neural potential of progenitors and their proliferation in the developing Xenopus laevis retina.

During retinal development, specific signalling mechanisms are thought to underlie important regional differences in progenitor proliferation and differentiation. The rate of progenitor proliferation increases to provide sufficient numbers of cells for neural differentiation. Progenitors then trigger the expression of factors that are required for retinal neurogenesis. Sox2, a Group B1 Sox gene, is thought to be involved in neurogenesis in the developing retina as it is specifically expressed in this region. However, until now, the signals that control Sox2 expression have not been identified. Previous work has implicated various components of the Wnt/Frizzled signalling pathway — including the transmembrane receptor Fz5 — in retinal development, which indicates that this pathway might be a good starting point for determining the mechanisms involved in signalling neural potential.

Vetter and colleagues report that blocking Fz5 in X. laevis results in lower proliferation rates of progenitors, lack of expression of the proneural genes that are required for neurogenesis and a bias towards the non-neural fate of Müller glial cells in the developing retina. The action of Fz5, which was mediated through the canonical Wnt/β-catenin signalling pathway, did not directly influence the expression of progenital markers in the retina. Instead, the effects of blocking Fz5 resulted from a reduction in the expression of its downstream effector, Sox2, at the stage of optical vesicle formation, as inhibition of Sox2 produced similar effects to inhibition of Fz5. These results therefore indicate that both Fz5 and Sox2 are crucial for determining neural potential and the proliferation of progenitors.

As the authors predict, it is likely that further signalling mechanisms that influence the expression of Sox2, and additional factors necessary for progenitor proliferation, will be identified in future studies. Nevertheless, these results mark an important step in the identification of the molecular mechanisms that underlie the acquisition of neural potential in the developing CNS.