Xie Zhen, Yang Qinghu, Lan Fei, Kong Wei, Zhao Shuxuan, Sun Jinyi, Yan Yan, Quan Zhenzhen, Bai Zhantao, Qing Hong, Mao Jian, Ni Junjun
Beijing Life Science Academy (BLSA), Beijing, China.
Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China.
Commun Biol. 2025 Jul 23;8(1):1097. doi: 10.1038/s42003-025-08508-8.
Cathepsin B (CatB), a protease in endosomal and lysosomal compartments, plays a key role in neuronal protein processing and degradation, but its function in brain development remains unclear. In this study, we found that CatB is highly expressed in the cortex of E12.5-E16.5 mice. Morphological analysis revealed significant defects in cortical development in CatB knockout (KO) mice, particularly in layer 6. In vitro experiments showed that CatB deficiency notably impaired neuronal migration and development. Behaviorally, CatB KO mice displayed prominent depressive-like behaviors, and electrophysiological recordings demonstrated significantly reduced neuronal activity in layer 6 of the medial prefrontal cortex. Mechanistically, proteomics analysis revealed that CatB KO affected neuronal migration and axonal growth, and decreased the expression of key transcription factors involved in neuronal development, particularly PEG3. Deficiency of PEG3 also significantly impaired neuronal migration and development. Our findings uncover a role for CatB in cortical development and suggest a mechanism linking CatB deficiency with depression and developmental defects through the destabilization of PEG3.
组织蛋白酶B（CatB）是一种存在于内体和溶酶体中的蛋白酶，在神经元蛋白质加工和降解中起关键作用，但其在脑发育中的功能仍不清楚。在本研究中，我们发现CatB在E12.5-E16.5小鼠的皮质中高表达。形态学分析显示，CatB基因敲除（KO）小鼠的皮质发育存在显著缺陷，尤其是在第6层。体外实验表明，CatB缺乏显著损害神经元迁移和发育。行为学上，CatB KO小鼠表现出明显的抑郁样行为，电生理记录显示内侧前额叶皮质第6层的神经元活动显著降低。机制上，蛋白质组学分析显示，CatB KO影响神经元迁移和轴突生长，并降低了参与神经元发育的关键转录因子的表达，特别是PEG3。PEG3的缺乏也显著损害神经元迁移和发育。我们的研究结果揭示了CatB在皮质发育中的作用，并提出了一种通过PEG3的不稳定将CatB缺乏与抑郁和发育缺陷联系起来的机制。
