CYFIP1 governs the development of cortical axons by modulating calcium availability

The human CYFIP1 gene is linked to Autism Spectrum Disorder (ASD) and Schizophrenia (SCZ), both associated with brain connectivity defects and corpus callosum abnormalities. Previous studies demonstrated that Cyfip1-heterozygous mice exhibit diminished bilateral functional connectivity and callosal defects-resembling observations in ASD and SCZ patients. Here, we demonstrate that CYFIP1 is crucial for cortical axonal development and identify insufficient calcium uptake as the pivotal mechanism. In vivo, Cyfip1 heterozygosity delays callosal axon growth and arborization. Additionally, Cyfip1-deficient cortical neurons and axons have reduced intracellular calcium, along with impaired mitochondria morphology, activity, and motility. Mechanistically, CYFIP1 binds and stabilises the mRNA of specific voltage-gated calcium channel subunits, explaining the decreased calcium concentration in Cyfip1^+/- cells. Notably, elevating intracellular calcium rescues delayed axonal growth and mitochondrial defects in Cyfip1-deficient neurons. These findings highlight that, by regulating mRNA metabolism, CYFIP1 ensures proper callosal development, offering insights into brain connectivity disruptions underlaying neurodevelopmental disorders.