Hancock, M. B. | bioRxiv Science

bioRxiv2025

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

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.

neuroscience↗

bioRxiv2025

Multi-omic analyses identify molecular targets of Chd7 that mediate CHARGE syndrome model phenotypes

CHARGE syndrome is a developmental disorder that affects 1 in 10,000 births, and patients exhibit both physical and behavioral characteristics. De novo mutations in CHD7 (chromodomain helicase DNA binding protein 7) cause 67% of CHARGE syndrome cases. CHD7 is a DNA-binding chromatin remodeler with thousands of predicted binding sites in the genome, making it challenging to define molecular pathways linking loss of CHD7 to CHARGE phenotypes. To address this problem, here we used a previously characterized zebrafish CHARGE model to generate transcriptomic and proteomic datasets from larval zebrafish head tissue at two developmental time points. By integrating these datasets with differential expression, pathway, and upstream regulator analyses, we identified multiple consistently dysregulated pathways and defined a set of candidate genes that link loss of chd7 with disease-related phenotypes. Finally, to functionally validate the roles of these genes, CRISPR/Cas9-mediated knockdown of capgb, nefla, or rdh5 phenocopies behavioral defects seen in chd7 mutants. Our data provide a resource for further investigation of molecular mediators of CHD7 and a template to reveal functionally relevant therapeutic targets to alleviate specific aspects of CHARGE syndrome. Summary StatementWe have identified Chd7 target genes capgb, nefla, and rdh5 that mediate CHARGE model phenotypes from transcriptomic and proteomic analysis of chd7 wild type, heterozygous, and homozygous mutant zebrafish brain tissue at two developmental time points.

neuroscience↗