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

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, Wt1^cKO 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 Wt1^cKO 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.