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PD-L1/PD-1 checkpoint pathway regulates astrocyte morphogenesis and myelination during brain development

Molecular Psychiatry volume 30, pages 3895–3911 (2025)Cite this article

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Summary

Programmed cell death protein 1 (PD-1) and its primary ligand PD-L1 are integral components of a significant immune checkpoint pathway, widely recognized for its central role in cancer immunotherapy. However, emerging evidence highlights their broader involvement in both the central and peripheral nervous systems. In this study, we demonstrate that PD-L1/PD-1 signaling in astrocytes during mouse brain development regulates astrocyte maturation and morphogenesis via the MEK/ERK pathway by targeting the downstream effector cysteine and glycine rich protein 1 (CSRP1). This enhanced astrocyte morphological complexity results in increased end-foot coverage of blood vessels. Additionally, aberrant secretion of CSRP1 by astrocytes interacts with oligodendrocyte precursor cells (OPCs) membrane proteins annexin A1 (ANXA1) and annexin A2 (ANXA2), leading to the exclusion of migrating OPCs from blood vessels. This disruption in OPC migration and differentiation results in abnormal myelination and is associated with cognitive deficits in the mice. Our results provide critical insights into the function of PD-L1/PD-1 signaling in astrocyte-OPC interactions and underscore its relevance to glial cell development and pathogenesis in neurodevelopmental disorders.

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Fig. 1: Astrocyte-derived PD-1 deficiency disrupts astrocyte populations.
Fig. 2: Increased morphological complexity of astrocytes induced by PD-1 deficiency.
Fig. 3: Astrocyte endfoot formation is related to the termination of OPC perivascular migration, and the absence of PD-1 disrupts this process.
Fig. 4: Disruption of astrocyte morphogenesis impairs myelination during brain development.
Fig. 5: Spatial learning memory and cognitive flexibility are impaired in Pd1cKO-Aldh1l1 mice.
Fig. 6: Regulation of astrogenesis by the MEK-ERK signaling axis through upregulation of CSRP1.
Fig. 7: Astrocytes regulate OPCs detachment from blood vessels through CSRP1-ANXA1/ANXA2 interactions.

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Data availability

Sequencing data have been deposited in the Gene Expression Omnibus website with accession number GSE272614. This paper does not report original code.

Code availability

Sequencing data have been deposited in the Gene Expression Omnibus website with accession number GSE272614. This paper does not report original code.

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Acknowledgements

We gratefully thank Bin Zhou (Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences) for providing PDGFRα-GFP mice. This work was supported by grants from the National Natural Science Foundation of China (32450088, 92368203, 32230040, 92468302), the National Key R&D Program of China (2024YFA1802600, 2024YFA1802202, 2021YFA1101402, 2024YFA1107500, and 2023YFA1801500), the Key Laboratory of Organ Regeneration and Reconstruction, Chinese Academy of Sciences (2024KF04), and the Initiative Scientific Research Program, Institute of Zoology, Chinese Academy of Sciences (2024IOZ0104 and 2023IOZ0304).

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  1. These authors contributed equally: Yanyan Wang, Mengtian Zhang.

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  1. Key Laboratory of Organ Regeneration and Reconstruction, Chinese Academy of Sciences, Beijing, 100101, China

    Yanyan Wang, Mengtian Zhang, Tianyu Zhang, Shukui Zhang, Fen Ji, Jie Qin, Hong Li & Jianwei Jiao

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Yanyan Wang, Mengtian Zhang, Tianyu Zhang, Shukui Zhang, Fen Ji, Jie Qin, Hong Li & Jianwei Jiao

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Contributions

YW and JJ designed the study. YW conducted the experiments and drafted the manuscript. MZ performed the data analysis with contributions from all authors. TZ carried out mouse genotype identification. SZ provided insights on data analysis. FJ advised on experimentation and manuscript writing. JQ was responsible for animal care. HL provided some advice about experiences. JJ supervised the project and secured funding.

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Correspondence to Jianwei Jiao.

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Wang, Y., Zhang, M., Zhang, T. et al. PD-L1/PD-1 checkpoint pathway regulates astrocyte morphogenesis and myelination during brain development. Mol Psychiatry 30, 3895–3911 (2025). https://doi.org/10.1038/s41380-025-02969-3

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