
CNTN4 contributes to cortical development and controls neural elongation through its interaction with APP.


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The neuronal cell adhesion molecule contactin-4 (CNTN4) has been genetically linked to autism spectrum disorders (ASD) and other psychiatric disorders. The Cntn4 -deficient mouse model has previously shown that CNTN4 has important roles in axon guidance and synaptic plasticity in the hippocampus. However, the pathogenesis and functional role of CNTN4 in the cortex have not yet been investigated.

Using Nissl staining, immunohistochemistry and Golgi staining the motor cortex of Cntn4-/- mice was analysed for abnormalities. Interacting partners of CNTN4 were identified by immunoprecipitation and mass spectrometry. Further analysis of the interaction between CNTN4 and APP utilised knockout human cells generated via CRISPR-Cas9 gene editing.

Our study newly identified reduced cortical thickness in the motor cortex of Cntn4-/- mice, but cortical cell migration and differentiation were unaffected. Significant morphological changes were observed in neurons in the M1 region of the motor cortex, indicating that CNTN4 is also involved in the morphology and spine density of neurons in the motor cortex. Furthermore, mass spectrometry analysis identified an interaction partner for CNTN4, and we confirmed an interaction between CNTN4 and APP. Knockout human cells of CNTN4 and/or APP revealed a relationship between CNTN4 and APP.

This study demonstrates that CNTN4 contributes to cortical development, and that its binding and interplay with APP controls neural elongation. This is an important finding for understanding the function of APP, a target protein for Alzheimer’s disease. The binding between Cntn4 and APP, which is involved in neurodevelopment, is essential for healthy nerve outgrowth.

### Competing Interest Statement

The authors have declared no competing interest.

CNTN4 Modulates Neural Elongation Through Interaction with APP