京都大学Mineko Kengaku小组近日取得一项新成果。经过不懈努力，他们研究出限制性迁移诱导发育中的神经元非致死性DNA损伤。2026年6月17日出版的《自然》杂志发表了这项成果。

在这里，研究组证明了神经元在发育中的大脑和小脑皮层的迁移伴随着大量的DNA双链断裂（DSBs），这是由于在通过狭窄间隙时的机械应力造成的。与许多其他迁移细胞相反，这些DSBs发生时没有可检测到的核膜破裂。受限的迁移增加了拓扑异构酶-IIβ共价结合的DSBs，并且这些病变在脑发育期间通过非同源的末端连接进行修复，而不会导致细胞死亡。

基因组测序显示，DSBs倾向于发生在转录不活跃的区域。在神经元迁移开始时，连接酶IV的缺失导致DSB在小脑神经元中持续积累，与突触功能、神经元发育、应激和免疫反应相关基因的转录发生适度变化。突变的小鼠在以后的生活中会出现轻微的运动缺陷，这表明在正常大脑发育过程中产生的DNA损伤如果不加以修复，会造成潜在的疾病风险。

据介绍，迁移细胞往往具有软核，可变形并穿透狭窄的空间。迁移过程中广泛的核变形可导致癌细胞的核包膜破裂和DNA损伤，这可能有助于肿瘤进展过程中的恶性转化。然而，DNA损伤在生理迁移中的重要性尚不清楚。

附：英文原文

Title: Confined migration induces non-lethal DNA damage in developing neurons

Author: Zhang, Zhejing, Canela, Andres, Kurisu, Junko, Zou, Peilin, Kawaue, Takumi, Nakazawa, Naotaka, Takeda, Noriko, Saeki, Mai, Utsunomiya, Masaki, Bilgic, Merve, Ishidate, Fumiyoshi, Grenci, Gianluca, Furuta, Takahiro, Kishi, Yusuke, Sasanuma, Hiroyuki, Kengaku, Mineko

Issue&Volume: 2026-06-17

Abstract: Migratory cells tend to have soft nuclei that deform and penetrate narrow spaces1,2. Extensive nuclear deformation during migration can cause nuclear-envelope rupture and DNA damage in cancer cells, which may contribute to malignant transformation during tumour progression3,4,5,6. However, the importance of DNA damage in physiological migration is less well understood. Here we demonstrate that the migration of neurons in developing cerebral and cerebellar cortices is accompanied by massive DNA double-stranded breaks (DSBs) due to mechanostress during passage through narrow interstitial spaces. In contrast to many other migratory cells, these DSBs occur without detectable nuclear envelope rupture. Confined migration increases topoisomerase-IIβ covalently bound DSBs, and these lesions are repaired through non-homologous end-joining during brain development without causing cell death. Genome sequencing revealed that DSBs tend to occur at transcriptionally inactive regions. The deletion of ligase IV at the onset of neuronal migration leads to persistent DSB accumulation in cerebellar neurons with moderate transcriptional changes in genes related to synaptic function, neuronal development and stress and immune responses. The mutant mouse develops mild motor deficits in later life, suggesting that the DNA damage generated during normal brain development poses a potential disease risk if left unrepaired.

DOI: 10.1038/s41586-026-10648-8

Source: https://www.nature.com/articles/s41586-026-10648-8

期刊信息

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504

官方网址：http://www.nature.com/

投稿链接：http://www.nature.com/authors/submit_manuscript.html