Wnt signalling is involved in numerous aspects of neural development, but it has not previously been implicated in axonal outgrowth. Now, Wang et al. have filled this gap in its functional repertoire, by showing that the Wnt receptor frizzled 3 (Fz3) is required for the development of major axonal tracts in the mammalian forebrain.

The authors knocked out the fz3 gene in mice, and found that four axonal tracts were missing — the thalamocortical, corticothalamic and nigrostriatal tracts, and the anterior commissure, which connects the left and right hemispheres of the brain. The corpus callosum was also absent in some cases. The mutation did not seem to cause any primary defects in the proliferation or survival of neuronal precursors, so it is unlikely that the phenotype resulted simply from the loss of neurons that give rise to the axonal tracts.

Wang et al. asked whether the fz3 mutation affects the intrinsic ability of forebrain neuronal precursors to develop axons. They found that, when these cells were isolated in culture, they readily adopted a typical neuronal morphology, with a full complement of axons and dendrites. So, it is more likely that the mutation affects the neuron's ability to interpret signals from its environment. The authors suggest that Fz3 might protect the neuron against signals that inhibit axonal outgrowth.

Another clue to the function of Fz3 came from studies in Drosophila. The Drosophila Fz protein regulates cell polarity, and in the wing epithelium, it determines the point on the cell surface from which a hair will grow. Therefore, another possibility is that Fz3 could determine the direction of neurite outgrowth, perhaps by regulating the neuronal cytoskeleton. This hypothesis could be tested by examining the subcellular localization of Fz3.

These findings point to a new direction for studying Wnt signalling in neural development. It will be interesting to delve into the mechanisms by which Fz3 controls axonal outgrowth, and to find out whether any other members of the frizzled family have similar functions in other regions of the nervous system.