Targeting miR-335-3p restores neural stem cell proliferation and ameliorates cognitive impairment in gestational dexamethasone-exposed offspring

In this study, we analyzed the miRNA expression profile in hippocampal neural stem cells (NSCs) from gestational synthetic GC analog dexamethasone (DEX) exposure (GDE) offspring mice, and found that miR-335-3p expression was significantly downregulated.

Functional experiments demonstrated that miR-335-3p specifically reverses the inhibitory effect of DEX on NSC proliferation without affecting their differentiation capacity. Mechanistic studies revealed that DEX activates the glucocorticoid receptor (GR) to directly suppress miR-335-3p transcription, which in turn relieves its targeted inhibition of PTEN, ultimately impairing NSC proliferation and cognitive function. This DEX/miR-335-3p/PTEN regulatory axis is highly conserved in human embryonic stem cells (hESCs)-derived 2D NSCs and 3D cerebral organoids.