Cyfip2 mediates sensorimotor integration of visual input through Rac1-dependent actin remodeling

Abstract

Sensorimotor integration of visual input is essential for adaptive behaviors such as navigation, hunting, and escape from danger, yet our understanding of the developmental mechanisms that assemble these visuomotor circuits remains incomplete. Cytoplasmic FMRP-interacting protein 2 (cyfip2) is a key factor in retinotectal axon guidance in zebrafish larvae, and it has conserved roles in regulating actin dynamics and mRNA translation. Variants in human CYFIP2 cause neurodevelopmental disabilities including vision deficits, but how it functions to shape visually-driven behavior is unclear. Here we measured multiple visually-mediated behaviors, brain-wide activity, and conditional rescue of behavioral defects in larval zebrafish to define cyfip2s roles in assembling visual sensorimotor circuits. cyfip2 mutants display severe deficits in prey capture and dark and light flash responses, despite normal optokinetic responses, indicating intact retinal phototransduction but disrupted downstream sensorimotor integration. Both spontaneous and stimulus-evoked neuronal activity are reduced in the optic tectum of cyfip2 mutants, as measured by phospho-ERK immunostaining and pan-neuronal calcium, consistent with impaired functional input from retinal ganglion cells. Finally, using conditional transgenic alleles to temporally control Cyfip2 expression, we identified a critical window from 30-50 hours post-fertilization during which Cyfip2 acts through Rac1-dependent actin polymerization but not FMRP-mediated translation to establish visual behavior circuits. Together, these findings define how and when Cyfip2 acts as a critical organizer of vertebrate visual circuit development, providing mechanistic insight into the visual and motor deficits in human subjects with variants in CYFIP2.