240: CYFIP1 controls cortical axon development by modulating calcium

Ricci C et al., Nature Communications - Reduction of CYFIP1 delays callosal axon growth and arborization by lowering intracellular calcium and impairing mitochondrial function. Key terms: cyfip1, axon development, calcium, mitochondria, callosal connectivity.

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:
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Article title:
CYFIP1 governs the development of cortical axons by modulating calcium availability

First author:
Ricci C

Journal:
Nature Communications

DOI:
10.1038/s41467-025-65801-0

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;16:10764. 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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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-26.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript segments covering in vivo axon development timing, calcium homeostasis, mitochondrial changes, CYFIP1-Hu interactions with CaV channel subunit mRNAs, and rescue experiments (ionomycin and VGCC agonists).
- transcript topics: CYFIP1 background and 15q11.2 CNVs; CYFIP1 dual roles: WRC actin regulation and translational repression; in vivo IUE and postnatal axon development timing (P5, P15, P30); mitochondrial density, motility, and morphology in Cyfip1+/- axons; intracellular Ca2+ dysregulation and mitochondrial function; CYFIP1 association with Hu proteins and regulation of CaV channel subunit mRNAs (CACNA1C, CACNA1E, CACNA1I)

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- CYFIP1 haploinsufficiency...

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