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Brain-specific Wt1 deletion leads to depressive-like behaviors in mice via the recruitment of Tet2 to modulate Epo expression

Molecular Psychiatry volume 26, pages 4221–4233 (2021)Cite this article

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Abstract

Major depressive disorder (MDD) is the most common psychiatric disease worldwide. The precise molecular and cellular mechanisms underlying this disorder remain largely unknown. Wilms’ tumor 1 (Wt1), a transcription factor, plays critical roles in cancer and organ development. Importantly, deletion of the 11p13 region that contains the WT1 gene is a major cause of WARG syndrome (Wilms’ tumor, aniridia, genitourinary anomalies, and mental retardation), which is characterized by psychiatric disease, including depression. However, the roles and mechanisms of WT1 in embryonic neurogenesis and psychiatric disease remain unclear. Here, we demonstrate that the brain-specific deletion of Wt1 results in abnormal cell distribution during embryonic neurogenesis, which is accompanied by enhanced proliferation of neural progenitors and reduced neuronal differentiation. Moreover, neurons exhibit abnormal morphology during cortical development following Wt1 ablation. Furthermore, Wt1cKO mice exhibit depressive-like behaviors, including immobility, despair, and anhedonia. Mechanistically, Wt1 recruits Tet2 to the promoter of erythropoietin (Epo), which results in enhanced 5-hydroxymethylcytosine (5hmC) levels and the promotion of Epo expression. Either Epo plasmid electroporation or Epo protein injection can partially restore the deficiency caused by Wt1 deletion. Importantly, administration of Epo to both embryos and adults can ameliorate the depressive-like behavior of Wt1cKO mice. In addition, WT1 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 Wt1 in embryonic neurogenesis and behavioral modulation, which could contribute to the understanding of MDD etiology and therapy.

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Fig. 1: Wt1 deficiency results in impaired neurogenesis.
Fig. 2: Wt1 deficiency leads to depressive-like behaviors.
Fig. 3: Wt1 regulates Epo expression by recruiting Tet2, thereby enhancing the 5hmC levels on the Epo promoter.
Fig. 4: Deficiency caused by Wt1 depletion can be partially rescued by Epo.
Fig. 5: Epo administration ameliorates depressive-like behavior in Wt1cKO mice.

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Acknowledgements

We thank all members in our lab for their valuable suggestions. We also thank Shiwen Li, Hua Qin, Xili Zhu, and Xuepei Lei for the help in confocal imaging and behavioral analysis. This work was supported by grants from the National Key R&D Program of China (2019YFA0110300), the CAS Strategic Priority Research Program (XDA16020602), the National Science Foundation of China (81825006, 31730033, and 31621004), Key deployment projects of the Chinese Academy of Sciences (ZDRW-ZS-2017-5), and K.C. Wong Education Foundation.

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Authors and Affiliations

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

    Fen Ji, Wenwen Wang, Chao Feng, Fei Gao & Jianwei Jiao

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

    Fen Ji, Chao Feng, Fei Gao & Jianwei Jiao

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

    Wenwen Wang

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

    Chao Feng

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

    Jianwei Jiao

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FJ performed the experiments, analyzed the results, and wrote the manuscript. WW and CF provided the help in the experiment performance. FG provided the Wt1fl/fl mice and helped in Wt1 antibody test. JJ supervised the project and provided the funding support.

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Correspondence to Fen Ji or Jianwei Jiao.

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Ji, F., Wang, W., Feng, C. et al. Brain-specific Wt1 deletion leads to depressive-like behaviors in mice via the recruitment of Tet2 to modulate Epo expression. Mol Psychiatry 26, 4221–4233 (2021). https://doi.org/10.1038/s41380-020-0759-8

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