The Wnt pathway is involved in a wide array of biological processes during development and is deregulated in many pathological scenarios. In neurons, Wnt proteins promote both axon extension and repulsion, but the molecular mechanisms underlying these opposing axonal responses are unknown. Here, we show that Wnt5a is expressed at the optic chiasm midline and promotes the crossing of retinal axons by triggering an alternative Wnt pathway that depends on the accumulation of βcatenin but does not activate the canonical pathway. In ipsilateral neurons, the transcription factor Zic2 switches this alternative Wnt pathway by regulating the expression of a set of Wnt receptors and intracellular proteins. In combination with this alternative Wnt pathway, the asymmetric activation of EphB1 receptors at the midline phosphorylates βcatenin and elicits a repulsive response. This alternative Wnt pathway and its Zic2-triggered switch may operate in other contexts that require a two-way response to Wnt ligands.

Wnt 通路在发育过程中涉及广泛的生物过程，并且在许多病理情况下被解除管制。在神经元中，Wnt 蛋白促进轴突延伸和排斥，但这些相反轴突反应的分子机制尚不清楚。在这里，我们表明 Wnt5a 在视交叉中线表达，并通过触发依赖于 βcatenin 积累但不激活经典途径的替代 Wnt 途径来促进视网膜轴突的交叉。在同侧神经元中，转录因子 Zic2 通过调节一组 Wnt 受体和细胞内蛋白的表达来转换这种替代的 Wnt 通路。结合这种替代的 Wnt 途径，中线 EphB1 受体的不对称激活使 β 连环蛋白磷酸化并引发排斥反应。这种替代的 Wnt 途径及其 Zic2 触发的开关可能在需要对 Wnt 配体进行双向响应的其他环境中运行。