Differential activation of a novel non-canonical, ß-catenin-dependent WNT pathway controls axon guidance decisions at the midline

Abstract

Resumen del póster presentado al European Developmental Biology Congress (EDBC), celebrado en Alicante del 23 al 26 de octubre de 2019.También presentado al 3rd AXON-meeting, celebrado en Alicante (España) del 11 al 13 de septiembre de 2019.The Wnt pathway is an essential signaling cascade that regulates many developmental processes including cell proliferation, differentiation and migration as well as axon extension and pathfinding. However, it is still debated which of the two Wnt pathways ⎯ the canonical pathway that involves β-catenin-dependent transcriptional activity or the non-canonical that is independent of β-catenin activity during axon guidance decisions. Here, we show that Wnt5a expressed at the optic chiasm midline enhances the growth of contralaterally-projecting axons independently of β-catenin-mediated transcription and therefore of the canonical pathway. However, we also observe that Wnt5a signaling promotes the accumulation of β-catenin in the growth cone and that interfering with this accumulation stalls the axon of the contralateral neurons at the chiasm indicating that midline crossing requires β-catenin. Strikingly, this positive response of contralateral axons to Wnt5a is switched off upon ectopic expression of the transcription factor Zic2, the main determinant of axon midline avoidance. Transcriptome and chromatin occupancy screens verified that Zic2 controls this Wnt5a-response switch. Our analyses retrieve a set of genes, Fzd8, Apc2, Diversin and Lgr5, that convert the axonal response to Wnt5a from positive to negative. Overall we show that axon steering at the midline requires the inhibition of the Wnt5a-positive signaling to prevent crossing, a signal concomitant with the activation of the Eph/ephrin-repulsive signaling. Our findings clarify outstanding questions concerning the implication of Wnt signaling pathways in axon pathfinding and contribute to a better understanding of the participation of these pathways in other developmental and oncogenic scenarios.Peer reviewe