When growth cones reach their synaptic targets, they must both send and receive signals in order to promote formation of mature synapses. We know little about the identity of such signals, but a recent paper (Hall, A.C., Lucas, F.R. & Salinas, P.C. Cell 100, 525–535, 2000) offers provocative evidence that WNT-7a may be one such molecule. The WNT factors are a family of secreted signaling proteins, and are known to be involved in early developmental patterning. Several are also expressed in the brain, and the presence of WNT-7a in cerebellar granule cells during the period of synaptogenesis prompted the authors to examine a possible role in this process.

Hall et al. studied the formation of synapses between mossy fibers, originating in the pons, and granule cells. Cultured granule cells secrete factors that induce remodeling of pontine axons in vitro; the effects include a spreading of the growth cones, changes in their cytoskeletal structure and an increase in filopodial length. These effects were blocked by an antagonist of WNT signaling, and were mimicked by conditioned medium containing WNT-7a (the figure shows a treated growth cone, stained for GAP-43, red, and tubulin, green). Remodeling could also be induced by low concentrations of lithium, which mimics WNT signaling by inhibiting a downstream kinase called GSK-3β. Finally, mice lacking WNT-7a show a delay in the formation of mossy fiber-granule cell synapses in vivo. The synapses do form eventually, suggesting that other members of the WNT family might be able to substitute for WNT-7a, but the phenotype nevertheless indicates that WNT-7a is involved in this process. It will be interesting to determine whether WNT factors play similar roles at other synapses, and whether they are also involved in adult plasticity. It will also be interesting to know whether any of the clinical effects of lithium (used to treat manic depression) can be attributed to its effects on WNT signaling.