CYFIP1 governs the development of cortical axons by modulating calcium availability.

Scientists studied a gene called CYFIP1 that's linked to autism. They found this gene helps brain cells grow connections between the two sides of the brain. When the gene doesn't work properly, brain cells can't take in enough calcium, which they need to grow properly. This might explain why some people with autism have differences in how their brain is connected.

This study investigated how CYFIP1, a gene linked to autism spectrum disorder and schizophrenia, affects brain development. Using mouse models, researchers found that reduced CYFIP1 function delays the growth of axons that connect brain hemispheres (corpus callosum). The mechanism involves CYFIP1's role in stabilizing mRNA for calcium channel proteins. When CYFIP1 is deficient, neurons have reduced calcium levels and impaired mitochondrial function, leading to delayed axonal development.

Importantly, restoring calcium levels rescued the developmental defects, suggesting calcium regulation is crucial for proper brain connectivity in neurodevelopmental disorders.

This research identifies calcium regulation as a potential therapeutic target for neurodevelopmental disorders involving brain connectivity defects. The findings may inform future treatment strategies aimed at supporting proper axonal development, though clinical applications require extensive further research and validation.

Study conducted in mouse models and cell cultures rather than humans. Sample sizes not reported. Clinical translation of calcium-based interventions requires further validation. Long-term effects and safety of calcium modulation approaches not established.

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 Cyfip1cells. 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.