Fanconi anemia pathway protects neuron–glial lineage integrity by resolving differentiation-induced endogenous DNA damage

Fanconi anemia (FA) is a congenital DNA repair disorder classically characterized by bone-marrow failure, yet emerging neurodevelopmental manifestations encompassing both congenital malformations and progressive neurodegeneration in FA patients remain mechanistically unexplained. Here we show that loss of the FA pathway selectively compromises neuroectodermal lineage progression in human cellular models, leading to impaired neuronal morphology, defective expression of neuronal and oligodendroglial markers, mitochondrial dysfunction, and defective electrophysiology. Mechanistically, transcriptional reprogramming during neural differentiation triggers a metabolic surge of endogenous formaldehyde, resulting in the accumulation of DNA-protein crosslinks (DPCs) and subsequent cell apoptosis in FANCL–/– cells.

These defects are effectively rescued by restoring either FANCL or the formaldehyde-detoxifying enzyme ADH5. Moreover, conditioned media from FANCL–/– neural culture induces a reactive astrogliosis-like response in recipient cells, supporting a non-cell autonomous pro-inflammatory component. Together, our findings establish the FA pathway as a critical safeguard of neurodevelopment, coordinating both intrinsic lineage maturation and extrinsic paracrine homeostasis.

We thank the Core Facilities at Life Sciences Institute and Zhejiang University School of Medicine for providing technical support. We thank all the members of the LL laboratory for valuable discussions and insightful suggestions. This work was supported by the National Key Research and Development Program of China (2022YFA1302800 to LL) and the National Natural Science Foundation of China (81930030 to HM).

Life Sciences Institute, Zhejiang University, Hangzhou, China Siqian Shi, Jinghang Wu, Zhilin Wang, Can Yi, Landing Li, Jiayi Wang, Fan Yang, Yajing Xiao, Sirui Cheng, Xianghuijun Yin, Xinxin Wang & Lei Li Department of Neurology of Second Affiliated Hospital and Liangzhu Laboratory, School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, China Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Hangzhou, China The authors declare no competing interests. Statement: During the preparation of this work, the author(s) used generative AI for the sole purpose of readability and language syntax proofing of the manuscript. After using this tool/service, the author thoroughly reviewed and edited the content and takes full responsibility for the content of the published article.

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