Ubiquitination regulates a myriad of eukaryotic signaling cascades by modifying substrate proteins, thereby determining their functions and fates. In this perspective, we discuss current challenges in investigating the ubiquitin system in the developing brain. We foster the concept that ubiquitination pathways are spatiotemporally regulated and tightly intertwined with molecular and cellular transitions during neurogenesis and neural circuit assembly. Focusing on the neurologically highly relevant class of homologous to E6AP C-terminus (HECT) ubiquitin ligases, we propose cross-disciplinary translational approaches bridging state-of-the-art cell biology, proteomics, biochemistry, structural biology and neuroscience to dissect ubiquitination in neurodevelopment and its specific perturbations in brain diseases. We highlight that a comprehensive understanding of ubiquitin signaling in the brain may reveal new horizons in basic neuroscience and clinical applications.

泛素化通过修饰底物蛋白来调节无数的真核信号级联反应，从而决定它们的功能和命运。从这个角度来看，我们讨论了当前研究发育中大脑中泛素系统的挑战。我们提出了泛素化途径受时空调控并与神经发生和神经回路组装过程中的分子和细胞转换紧密交织的概念。专注于与 E6AP C 末端 （HECT） 泛素连接酶在神经学上高度相关的一类泛素连接酶，我们提出了跨学科的转化方法，将最先进的细胞生物学、蛋白质组学、生物化学、结构生物学和神经科学联系起来，以剖析神经发育中的泛素化及其在脑疾病中的特异性扰动。我们强调，全面了解大脑中的泛素信号转导可能会揭示基础神经科学和临床应用的新视野。