A transcriptional switch in a novel non-canonical, ßcatenin dependent Wnt pathway controls axon midline decisions

During the establishment of neuronal connections, axons must correctly navigate long pathways to find their targets. By focusing on the guidance of visual axons at the midline, we describe for the first time that a switch in a novel branch of the Wnt pathway, which is not the canonical or the non-canonical, that controls axonal directionality. This finding conciliates the current debate about the participation of the Wnt pathways in axon pathfinding. We then identify the transcription factor (TF) Zic2 as the regulator of this switch and describe the entire set of genes regulated by it. Also, although previous genome-wide approaches have not retrieved the binding motif for this TF, we report here a de novo Zic2 binding motif that is located in promoter and intragenic regions. In addition, we find that the tyrosine kinase EphB receptor, which is one of the genes induced by Zic2, interferes with the Wnt pathway by phosphorylating betacatenin at the growth cone and inducing its asymmetric detachment from the membrane to promote axon steering. RNA-seq of Retinal ganglion cells (RGC) expressing GFP or Zic2, ChIP-seq of Zic2 in spinal cords and retina.