Regulation of Scn1b and Scn2a by BCL9 in cortical neurodevelopment and neuronal excitability

The convergence of oncology and neurodevelopmental research has uncovered compelling links between genetic factors and mental health. Among these, B-cell chronic lymphocytic leukemia/lymphoma 9 (BCL9), located on human chromosome 1q21.1, has been identified as a key oncogene in precursor B-cell acute lymphoblastic leukemia (B-ALL). Subsequent studies have established that Bcl9 promotes tumorigenesis through activation of the Wnt/β-catenin signaling pathway. Emerging evidence from human genetic studies further implicates common variants of Bcl9 in increased susceptibility to neurodevelopmental disorders, including schizophrenia and bipolar disorder. Despite growing interest in its role beyond cancer, the neurobiological functions of Bcl9 remain poorly defined. In this study, we systematically investigated the role of Bcl9 in neurodevelopment using mouse models. By employing in utero electroporation-mediated gene knockdown techniques and conditional knockout (cKO) mice, we demonstrate that Bcl9 deficiency disrupts Wnt-dependent signal transduction and leads to upregulation of voltage-gated sodium channel (Nav) expression, thereby results in increased sodium current density but paradoxically reduced action potential firing. Based on our experimental findings, Bcl9 and/or the Bcl9 complexes may regulate the promoter region of the Scn1b gene and the area near the exons of Scn2a. Collectively, our findings establish Bcl9 as a critical regulator of neuronal excitability and migration, providing a mechanistic framework that links ion channel dysregulation to the pathophysiology of neurodevelopmental disorders.