️ Episode 240: CYFIP1 controls cortical axon development by modulating calcium

In this episode of PaperCast Base by Base, we explore Reduction of CYFIP1 delays callosal axon growth and arborization by lowering intracellular calcium and impairing mitochondrial function

Study Highlights:
In vivo, Cyfip1+/- mice show delayed callosal axon growth at P5 and reduced axonal branching during P15 arborization that normalizes by P30. Cyfip1+/- cortical neurons have reduced cytosolic and mitochondrial calcium, larger and elongated mitochondria, increased mitochondrial density and motility, and decreased mitochondrial membrane potential and ATP at early stages. CYFIP1 associates with Hu proteins and binds mRNAs encoding Cav alpha-1 subunits (Cacna1c, Cacna1e, Cacna1i), stabilizing those transcripts and maintaining membrane protein levels in developing neurons and axons. Loss of CYFIP1 accelerates decay of these channel mRNAs, leading to reduced Cav protein abundance in axons and lower calcium availability. Restoring intracellular calcium with ionomycin or activating L-type channels (Bay-K-8644, nefiracetam) rescues axonal growth and mitochondrial defects in Cyfip1+/- neurons

Conclusion:
CYFIP1 ensures timely cortical callosal development by stabilizing mRNAs for voltage-gated calcium channel subunits to maintain intracellular calcium and mitochondrial function, and its haploinsufficiency may contribute to connectivity deficits linked to neurodevelopmental disorders

Music:
Enjoy the music based on this article at the end of the episode.

Reference:
Ricci C, Midroit MJ, Caicci F, Achsel T, Domínguez-Iturza N, Bagni C. CYFIP1 governs the development of cortical axons by modulating calcium availability. Nature Communications. 2025;16:10 764. https://doi.org/10.1038/s41467-025-65801-0

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Keywords: cyfip1, axon development, calcium, mitochondria, callosal connectivity

Chapters

• (00:00:00 ) - Deep Dive: The brain's dysfunctional wiring
• (00:02:10 ) - CYFIP1 governs the development of cortical axons by
• (00:07:16 ) - The bottleneck in MRNA production
• (00:08:03 ) - CIFIP1 deficiency in neurodevelopmental disorders
• (00:13:06 ) - CY FIP1 dysregulation in the brain