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CYFIP1 governs the development of cortical axons by modulating calcium availability
Carlotta Ricci1,2, Maëllie Julie Midroit1, Federico Caicci3
1Department of Fundamental Neurosciences, University of Lausanne, Vaud, Switzerland.
Nature Communications
|November 29, 2025
Summary
The CYFIP1 gene is vital for brain connectivity, as its deficiency impairs axonal development and calcium uptake. Restoring calcium levels in Cyfip1-deficient neurons rescues these defects, offering insights into neurodevelopmental disorders.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- The CYFIP1 gene is implicated in Autism Spectrum Disorder (ASD) and Schizophrenia (SCZ).
- CYFIP1 deficiency in mice mirrors brain connectivity and corpus callosum abnormalities seen in ASD and SCZ patients.
- Previous research indicated Cyfip1-heterozygous mice display reduced functional connectivity and callosal defects.
Purpose of the Study:
- To investigate the role of CYFIP1 in cortical axonal development.
- To identify the underlying molecular mechanisms, particularly focusing on calcium regulation.
- To explore potential therapeutic strategies by manipulating intracellular calcium levels.
Main Methods:
- In vivo studies using Cyfip1-heterozygous mouse models.
- Analysis of cortical neuron and axon development, including growth and arborization.
- Measurement of intracellular calcium levels, mitochondrial morphology, activity, and motility.
- Investigation of CYFIP1's interaction with voltage-gated calcium channel subunit mRNAs.
- Experimental manipulation of intracellular calcium levels in deficient neurons.
Main Results:
- Cyfip1 heterozygosity leads to delayed callosal axon growth and arborization.
- Cyfip1-deficient neurons exhibit reduced intracellular calcium concentrations.
- Mitochondrial morphology, activity, and motility are impaired in Cyfip1-deficient axons.
- CYFIP1 directly binds and stabilizes mRNAs of specific voltage-gated calcium channel subunits.
- Increasing intracellular calcium levels rescues axonal growth and mitochondrial defects in Cyfip1-deficient neurons.
Conclusions:
- CYFIP1 is essential for proper cortical axonal development and callosal formation.
- Insufficient calcium uptake, due to CYFIP1's regulation of calcium channel mRNAs, is a key mechanism in CYFIP1-related neurodevelopmental defects.
- Targeting intracellular calcium levels presents a potential therapeutic avenue for neurodevelopmental disorders associated with CYFIP1 dysfunction.
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