# The ErbB2–Dock7 Signaling Axis Mediates Excessive Cell Morphogenesis Induced by Autism Spectrum Disorder- and Intellectual Disability-Associated Sema5A p.Arg676Cys

## TL;DR

This study identifies a signaling pathway involving ErbB2 and Dock7 that causes abnormal neuron shape changes linked to autism and intellectual disability.

## Contribution

The study is the first to show that the ErbB2–Dock7 axis mediates excessive neuronal process elongation caused by a Sema5A mutation associated with ASD and ID.

## Key findings

- Knockdown of Dock7 or inhibition of ErbB2 reduced excessive neuronal process elongation in primary cortical neurons.
- Inhibition of ErbB2-Dock7 signaling decreased overactivation of downstream molecules Rac1 and Cdc42.
- Similar results were observed in the N1E-115 neuronal cell model.

## Abstract

Characterized by social communication deficits and the presence of restricted and repetitive behaviors, autism spectrum disorder (ASD) is a significant neurodevelopmental condition. Genetic studies have revealed a strong association between ASD and numerous mutations that alter the function of key proteins, either through activation or inactivation. These alterations are widely hypothesized to affect neuronal morphogenesis; however, a comprehensive understanding of the specific molecular cascades driving these cellular and symptomatic changes remains lacking. In this study, we report for the first time that signaling through the atypical Rho family guanine-nucleotide exchange factor (GEF) Dock7 and ErbB2, an activator acting upstream of Dock7, drives the excessive elongation of neuronal processes observed in association with the ASD- and intellectual disability (ID)-linked semaphorin-5A (Sema5A) Arg676Cys variant (p.Arg676Cys). Knockdown of Dock7 using short hairpin RNA or inhibition of ErbB2 kinase signaling with a specific chemical inhibitor reduced this excessive process elongation in primary cortical neurons. Similar results were obtained in the N1E-115 cell line, a neuronal cell model that undergoes neuronal morphological differentiation. Moreover, inhibition of ErbB2-Dock7 signaling specifically decreased the overactivation of the downstream molecules Rac1 and Cdc42. These findings indicate that the ErbB2–Dock7 signaling axis plays a role in mediating the aberrant neuronal morphology associated with the ASD- and ID-linked Sema5A p.Arg676Cys. Targeting this pathway may therefore offer a potential approach to addressing the molecular and cellular developmental challenges observed in ASD.