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Brain-specific Pd1 deficiency leads to cortical neurogenesis defects and depressive-like behaviors in mice

Cell Death & Differentiation volume 30, pages 2053–2065 (2023)Cite this article

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Abstract

Embryonic neurogenesis is tightly regulated by multiple factors to ensure the precise development of the cortex. Deficiency in neurogenesis may result in behavioral abnormalities. Pd1 is a well-known inhibitory immune molecule, but its function in brain development remains unknown. Here, we find brain specific deletion of Pd1 results in abnormal cortical neurogenesis, including enhanced proliferation of neural progenitors and reduced neuronal differentiation. In addition, neurons in Pd1 knockout mice exhibit abnormal morphology, both the total length and the number of primary dendrites were reduced. Moreover, Pd1cKO mice exhibit depressive-like behaviors, including immobility, despair, and anhedonia. Mechanistically, Pd1 regulates embryonic neurogenesis by targeting Pax3 through the β-catenin signaling pathway. The constitutive expression of Pax3 partly rescues the deficiency of neurogenesis in the Pd1 deleted embryonic brain. Besides, the administration of β-catenin inhibitor, XAV939, not only rescues abnormal brain development but also ameliorates depressive-like behaviors in Pd1cKO mice. Simultaneously, Pd1 plays a similar role in human neural progenitor cells (hNPCs) proliferation and differentiation. Taken together, our findings reveal the critical role and regulatory mechanism of Pd1 in embryonic neurogenesis and behavioral modulation, which could contribute to understanding immune molecules in brain development.

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Fig. 1: Pd1 is expressed in the embryonic brain and involves in the regulation of neurogenesis.
Fig. 2: Pd1 deficiency results in abnormal proliferation and differentiation of neural progenitor cells.
Fig. 3: Pd1 deficiency results in abnormal neuronal morphology.
Fig. 4: Pd1 deletion leads to depressive-like behaviors in mice.
Fig. 5: Pd1 regulates embryonic neurogenesis by targeting Pax3.
Fig. 6: Pd1 regulates Pax3 expression through AKT/GSK-3β/β-catenin signaling pathway.
Fig. 7: XAV939 administration ameliorates the abnormal behaviors in Pd1cKO mice.

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Data availability

RNA-seq data are available in GEO with the following accession number: GSE207712.

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Acknowledgements

We thank all members of our lab for their valuable suggestions. We also thank Shiwen Li, Lijuan Wang, Hua Qin, and Xili Zhu for their help in confocal imaging and behavioral analysis. This work was supported by grants from the National Key R&D Program of China (2019YFA0110301 and 2021YFA1101402), the National Natural Science Foundation of China (32230040, 81825006, and 92149304), and Guangdong Basic and Applied Basic Research Foundation (2022B1515120026).

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Authors and Affiliations

  1. State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China

    Fen Ji, Chao Feng, Jie Qin, Chong Wang, Dongming Zhang, Libo Su, Wenwen Wang, Mengtian Zhang, Hong Li, Changmei Liu, Zhaoqian Teng, Baoyang Hu & Jianwei Jiao

  2. Innovation Academy for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101, Beijing, China

    Fen Ji, Hong Li, Changmei Liu, Zhaoqian Teng, Baoyang Hu & Jianwei Jiao

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

    Fen Ji, Chao Feng, Jie Qin, Dongming Zhang, Mengtian Zhang, Changmei Liu, Zhaoqian Teng, Baoyang Hu & Jianwei Jiao

  4. Sino-Danish College at University of Chinese Academy of Sciences, 100049, Beijing, China

    Chao Feng & Jie Qin

  5. School of Life Sciences, University of Science and Technology of China, Hefei, 230026, Anhui, China

    Chong Wang

  6. Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 100053, Beijing, China

    Longbing Ma & Fengzeng Jian

  7. Department of Anesthesiology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China

    Weicheng Lu & Jingdun Xie

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  1. Fen Ji
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Contributions

FJ performed the experiments, analyzed the results, and wrote the manuscript. CF constructed the plasmids of Pd1 and Pdl1. JQ, CW, LS, WW, MZ, HL, LM, WL, CL, ZT, and BH provided help in the experiment performance. DZ provided help in human NSCs culture. FJ and JX supervised the project. JJ supervised the project and provided funding support.

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Correspondence to Fen Ji, Fengzeng Jian, Jingdun Xie or Jianwei Jiao.

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Ji, F., Feng, C., Qin, J. et al. Brain-specific Pd1 deficiency leads to cortical neurogenesis defects and depressive-like behaviors in mice. Cell Death Differ 30, 2053–2065 (2023). https://doi.org/10.1038/s41418-023-01203-3

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