Right-brain expression-biased wnt3 is vital in maintaining normal language function via combined functional genomic and genetic analysis

Language is a unique human capability with limited molecular understanding due to the lack of animal models and technical constraints. Transcriptomics analysis offers a comprehensive view of gene expression in specific tissues, aiding the understanding of their functions. However, such patterns have been underexplored in language-related regions of the human brain. This study conducts a comprehensive transcriptomic analysis of 125 samples from 13 language-related Brodmann areas (BAs) in both hemispheres of five human postmortem brains. The expression landscape of human language-related regions is mapped, revealing higher expression in the right hemisphere, notably BA45 (Broca’s area) and BA3/1/2 (ventral sensory-motor cortex). Integrative analysis of differentially expressed genes and language-relevant genetic discoveries provides insights into the rs62060948 locus. The findings suggest that the rs62060948-MYC-WNT3 axis plays a crucial role in language function in BA44 of the right hemisphere. Behavior tests in mice show that Wnt3 knockdown in the right auditory cortex leads to abnormal behaviors, confirming that imbalanced Wnt3 expression impacts language function. Pathway analysis indicates that Wnt3 maintains nervous system development through neuron ensheathment. This study enhances understanding of the molecular mechanisms underlying human language function and identifies potential targets for language disorder therapies.