Hif-1α regulation of the Tet1-β-catenin-Dicer1-miRNAs pathway is involved in depression-like behavior in prenatal hypoxic male offspring

Abstract

Prenatal hypoxia (PH) is a common complication of pregnancy, and it is strongly associated with psychiatric disorders such as depression and anxiety in the offspring. However, how prenatal hypoxia contributes to psychiatric disorders in the offspring is unclear. In this study, we established a model of prenatally hypoxic mice, where pregnant females were treated with hypoxia (10.5% O₂) during gestational days 12.5–17.5, while controls (CON) were kept in a normoxic (21% O₂) environment. Compared to CON offspring, PH male offspring exhibited depression-like behaviors. Prenatal hypoxia resulted in significantly higher protein level of the oxygen-sensitive subunit of hypoxia-inducible factor (Hif-1α) and lower levels of Ten-eleven translocated methylcytosine dioxygenase 1 (Tet1), β-catenin, and downstream Dicer1-miRNAs pathway associated with depressive behavior. Mechanistically, prenatal hypoxia leads to Hif-1α binding to Tet1, which inhibits β-catenin binding to Tet1, leading to an increase in ubiquitination-dependent degradation of β-catenin and down-regulation of the β-catenin-Dicer1-miRNAs pathway. In addition, administration of the β-catenin-specific agonist SKL2001 or overexpressing virus ameliorated the down-regulation of β-catenin-Dicer1-miRNAs signaling and depression-like behavior in PH male offspring. These findings suggest that Hif-1α and β-catenin competition for Tet1 binding is involved in depression-like behaviors in PH offspring, and this study provides important data on the molecular mechanisms by which prenatal hypoxia might be involved in adult psychiatric disorders of fetal origin.