During the development of the vertebrate eye, retinal ganglion cell axons converge on the optic disc, where they exit the eyeball to form the optic stalk. The mechanisms that guide these axons towards the optic disc are poorly understood — it was proposed that the disc itself might produce a long-range chemoattractant, but no such activity has been identified in this region. Now, Zhang and colleagues present evidence that graded expression of the transcription factor Zic3 induces the generation of a repulsive force, which channels retinal axons towards the optic disc.

Using in situ hybridization, the authors showed that the Zic3 gene is normally expressed in a gradient within the retina, with the highest concentration at the periphery and the lowest at the centre. They disrupted this gradient by transfecting the embryonic chick retina with a Zic3-expressing retroviral vector. This caused various axon guidance defects, including stalling of growth cones within the sites of transfection, and, less frequently, axons turning 180° to project back towards the periphery of the retina.

Next, Zhang et al. presented retinal ganglion cells in culture with the choice of growing on retinal membrane fragments that were transfected with either a control green fluorescent protein-expressing retroviral construct or the Zic3-expressing construct. When they were faced with alternating stripes of these two tissues, the cells extended axons preferentially on the control stripes. Similarly, when the cells were presented with alternating stripes of membrane from the centre and the periphery of the retina, most of their axons grew along the stripes from the centre of the retina.

Taken together, these findings indicate that Zic3-expressing tissue releases a factor that repels the axons of retinal ganglion cells. Zic3 is not the first Zic family member to be implicated in axon guidance in the visual system — Zic2 was recently shown to be involved in controlling axon crossing at the optic chiasm. As the Zic proteins are transcription factors, they presumably act by inducing the expression of guidance cues. So, to understand their roles in axon guidance, it will be important to identify their downstream targets.