Temporal tuning of actin nucleation by the repurposed DNA repair complex RAD51/fignl1 encodes distinct axon guidance decisions

Abstract

Axon guidance is essential for neural circuit assembly and function. While much of the repertoire of guidance cues and receptors is known, its limited diversity cannot fully explain the remarkable complexity of the brain connectome. How temporally ordered, context-dependent intrinsic programs shape the diversity of axonal responses to guidance signals remains poorly understood. We reveal how non-canonical Wnt5a signalling repurposes the DNA repair complex RAD51/fignl1 as a downstream integrator to control retinal ganglion cell axon decision-making at the midline. We demonstrate that differential RAD51/fignl1 expression and interaction dynamics between ipsilateral and contralateral axons tunes the magnitude and temporal dynamics of F-actin nucleation, thereby encoding their trajectory choice. Our findings establish temporal control of cytoskeletal dynamics as a key determinant of axon decision-making and thereby a fundamental layer of circuit wiring. They provide a potential mechanistic framework linking mutations in the DNA repair gene RAD51 to neurodevelopmental disorders with midline guidance defects.