The Role of HUWE1 on Mouse Neural Cell Proliferation and Zebrafish Neurodevelopment

The HECT, UBA, and WWE domain‐containing E3 ubiquitin protein ligase 1 ( HUWE1 ) gene is located on the X chromosome and has been implicated in neurodevelopmental disorders. However, the mechanisms by which HUWE1 dosage affects nervous system development remain poorly understood. In this study, we demonstrate that HUWE1 overexpression suppresses the proliferation of neural‐derived cells, induces apoptosis, and reduces G2/M phase progression. Mechanistically, HUWE1, as an E3 ubiquitin ligase, promotes the ubiquitination and degradation of key components of the Wnt/β‐catenin signaling pathway, including β‐catenin, DVL1, and CK1. In vivo, overexpression of huwe1 in zebrafish embryos resulted in abnormal brain development, reduced eye size, cardiac edema, and spinal curvature, showing developmental abnormalities relevant to neurodevelopmental phenotypes. These phenotypes were dose‐dependent and could be partially rescued by activation of Wnt/β‐catenin signaling pathway. Collectively, our findings demonstrate that HUWE1 overexpression disrupts neurodevelopment by negatively regulating the Wnt/β‐catenin signaling pathway. These results highlight the importance of HUWE1 dosage control in nervous system development and provide a rationale for further investigation of HUWE1 copy number variation in neurodevelopmental disorders.