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 delays callosal axon growth and arborization in vivo with normalization by P30
- Cyfip1+/- cortical axons show reduced cytosolic/axo-plasmic Ca2+ and altered mitochondrial function (density, motility, membrane potential, ATP at early stages)
- CYFIP1 binds and stabilizes mRNA of CaV channel subunits CACNA1C, CACNA1E, CACNA1I via Hu proteins, affecting axonal calcium entry
- CaV channel subunits (CaV1.2 CACNA1C, CaV2.3 CACNA1E, CaV3.3 CACNA1I) are reduced in membrane fractions at DIV3 in Cyfip1+/- neurons; later stages show normalization
- mRNA levels of CACNA1E and CACNA1I are significantly reduced in Cyfip1+/- neurons; CACNA1C shows a non-significant downward trend
- Ionomycin and VGCC agonists Bay-K-8644 and Nefiracetam rescue delayed axonal growth and mitochondrial defects

QC result: Pass.