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

Scientists studied a gene change linked to autism and found it makes brain cells grow in unusual ways. They discovered a specific pathway in cells (ErbB2-Dock7) that causes this abnormal growth. When they blocked this pathway in laboratory experiments, the brain cells grew more normally. This research helps explain how certain genetic changes might contribute to autism and could lead to new treatment approaches.

This laboratory study investigated how a specific genetic variant (Sema5A p.Arg676Cys) linked to autism and intellectual disability affects neuronal development. Researchers found that this variant causes excessive elongation of neuronal processes through the ErbB2-Dock7 signaling pathway. Using cultured neurons and a neuronal cell line, they demonstrated that blocking either ErbB2 or Dock7 reduced the abnormal cell growth patterns. The study also showed that this pathway overactivates downstream molecules Rac1 and Cdc42.

This research provides new insights into the molecular mechanisms underlying autism-related neuronal development abnormalities and suggests the ErbB2-Dock7 pathway as a potential therapeutic target.

Identifies ErbB2-Dock7 as a potential therapeutic target for autism associated with Sema5A variants. Suggests pathway-specific interventions may address neuronal development abnormalities. However, translation to clinical applications requires further validation in animal models and human studies before therapeutic development can proceed.

Study conducted only in laboratory cell cultures and neuronal cell lines. No human or animal model validation. Sample sizes not reported. Long-term effects and clinical translation unclear. Limited to one specific genetic variant.

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.