Peripheral gene dysregulation in Negr1-deficient mice: insights into possible links with affective behavior.

Introduction: Neuronal growth regulator 1 (NEGR1) is a brain-enriched membrane protein with mild expression in peripheral tissues such as adipose tissue and skeletal muscle. Genome-wide association studies have implicated NEGR1 as a risk factor for human diseases including obesity, autism, and depression, but its molecular function remains poorly understood.

Methods: To explore NEGR1's role in peripheral-to-brain communication, we conducted RNA-seq analysis on four peripheral tissues-intestine, skeletal muscle, liver, and epididymal white adipose tissue-collected from Negr1 knockout mice. Differentially expressed genes (DEGs) were identified and subjected to Gene Ontology (GO) enrichment analyses.

Results: The DEG analysis revealed dysregulation of ion channels and transporters, potentially contributing to AP-1-mediated inflammatory responses in peripheral tissues. Additionally, interleukin (IL)-17 signaling emerged as a key pathway that may mediate systemic inflammation in Negr1-deficient mice.

Discussion: These findings suggest a novel role for NEGR1 in modulating peripheral inflammatory responses and support the hypothesis that peripheral immune dysregulation may contribute to depressive-like behaviors in Negr1-deficient mice. This work enhances our understanding of NEGR1's function in peripheral tissues and its possible involvement in peripheral-central immune crosstalk relevant to psychiatric disorders.