Zhang Xiaofan, Chen Wei, Wang Yayu, Tu Xun, Zhang Xiangyu, Davis Ronald L, Jan Lily Yeh, Jan Yuh Nung
Department of Physiology and Howard Hughes Medical Institute, University of California at San Francisco; San Francisco, CA 94158, USA.
Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA.
bioRxiv. 2025 Sep 3:2025.08.29.673168. doi: 10.1101/2025.08.29.673168.
Neuronal remodeling is essential for sculpting neural circuits, and its disruption has been implicated in neurodevelopmental and neuropsychiatric disorders. Yet the molecular and cellular diversity of remodeling across neuron types remains incompletely understood. Here, we uncover a distinct remodeling mode in a subtype of dopamine neurons (DANs) critical for learning, memory, sleep, and locomotion. Unlike the stereotypical pruning-then-regrowth paradigm, these DANs undergo a transient axon overgrowth followed by selective pruning during metamorphosis. Remarkably, DAN axon pruning proceeds independently of canonical ecdysone signaling and instead involves neuron-intrinsic AKT-GSK3β signaling and extrinsic glial activity. Disruption of AKT-GSK3β signaling alters microtubule stability and impairs glial recruitment and clearance of axonal debris. Notably, the role of AKT-GSK3β is cell-type specific, underscoring mechanistic diversity in remodeling programs. These findings reveal an unexpected overgrowth-then-pruning developmental trajectory, establishing DANs as a powerful model to uncover the mechanisms underlying neuronal remodeling, circuit maturation, and neurodegeneration.
神经元重塑对于构建神经回路至关重要，其破坏与神经发育和神经精神疾病有关。然而，不同神经元类型之间重塑的分子和细胞多样性仍未完全了解。在这里，我们在对学习、记忆、睡眠和运动至关重要的多巴胺神经元（DANs）亚型中发现了一种独特的重塑模式。与典型的先修剪后再生模式不同，这些DANs在变态过程中经历短暂的轴突过度生长，随后进行选择性修剪。值得注意的是，DAN轴突修剪独立于经典的蜕皮激素信号传导，而是涉及神经元内在的AKT-GSK3β信号传导和外在的神经胶质活动。AKT-GSK3β信号传导的破坏会改变微管稳定性，并损害神经胶质细胞的募集和轴突碎片的清除。值得注意的是，AKT-GSK3β的作用具有细胞类型特异性，强调了重塑程序中的机制多样性。这些发现揭示了一种意想不到的先过度生长后修剪的发育轨迹，将DANs确立为揭示神经元重塑、回路成熟和神经退行性变潜在机制的有力模型。
