A neuronal Slit1-dependent program rescues oligodendrocyte differentiation and myelination under chronic hypoxic conditions
Oligodendrocyte maturation arrest in hypoxia-induced white matter injury (WMI) results in long-term neurofunctional disabilities of preterm infants. Although neurons are closely linked to myelination regulation, how neurons respond to the above process remains elusive. Here, we identify a compensatory role of neuronal Slit1-dependent signaling in protecting against hypoxia-induced hypomyelination and ameliorating motor and cognitive disabilities. Conditional ablation of Slit1 in neurons exacerbates hypoxia-induced hypomyelination but is negligible for developmental myelination. Secreted Slit1 from hypoxic neurons directly targets oligodendrocyte, acting through Robo2-srGAP1-RhoA signaling. Pharmacological inhibition of RhoA restores myelination and promotes neurofunctional recovery in adolescent mice. Notably, natural selection analysis and functional validation indicate an adaptive variant with higher Slit1 gene expression in the Tibetan population, which has low oxygen availability. Collectively, these findings show a neuronal Slit1-dependent program of OL differentiation and suggest that targeting the Slit1-Robo2 signaling axis may have therapeutic potential for treatment of preterm infants with hypoxic WMI.
Authors
- Qiuying Huang (ORCID: https://orcid.org/0000-0002-4224-0710)
- Shufang Jia
- Zhihao Zhou (ORCID: https://orcid.org/0000-0002-0746-1446)
- Zilong Qiu (ORCID: https://orcid.org/0000-0003-4286-3288)
- Daopeng Li
- Shuhua Xu (ORCID: https://orcid.org/0000-0002-1975-1002)
- Ximing Nian
- Jiazhong Lu (ORCID: https://orcid.org/0000-0002-8982-8255)
- Ren Xu (ORCID: https://orcid.org/0000-0001-6578-4553)
- Wenxiu Dai
- Yunshan Xiao
- Lu Yan (ORCID: https://orcid.org/0000-0001-8616-3529)
- Wanying Lei (ORCID: https://orcid.org/0000-0002-9153-9233)
- Nengyin Sheng (ORCID: https://orcid.org/0000-0003-3086-3950)
- Liang Zhang (ORCID: https://orcid.org/0000-0003-4528-2403)
- Qi Liu (ORCID: https://orcid.org/0000-0003-2608-6386)
- Xueqin Zhang (ORCID: https://orcid.org/0000-0002-1804-0102)
- Yanqiang Hou (ORCID: https://orcid.org/0000-0002-3736-8103)
- Xiaoyun Lu
- Xiujuan Zang (ORCID: https://orcid.org/0000-0001-7043-0194)
- Ailian Du (ORCID: https://orcid.org/0009-0007-8962-5312)
- Yanqin Zhu (ORCID: https://orcid.org/0000-0002-8257-6147)
- Liangkai Zheng (ORCID: https://orcid.org/0009-0001-5321-2715)
Institutions
- Kunming Institute of Zoology (CN)
- Xiamen University (CN)
- Fudan University (CN)
- Tongren Hospital (CN)
- Songjiang District Central Hospital (CN)
- Children’s Hospital of Fudan University Xiamen Branch (CN)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-03-20
- DOI
- https://doi.org/10.1016/j.celrep.2025.115467
- Citations
- 4
- Primary Topic
- Neurogenesis and neuroplasticity mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 5.27
Funders
- National Natural Science Foundation of China
- West Light Foundation of the Chinese Academy of Sciences
- Key Disciplines Construction Project of Shanghai Municipal