MicroRNA-495 Modulates Neuronal Layer Fate Determination by Targeting Tcf4

During cortical development, the differentiation potential of neural progenitor cells (NPCs) is one of the most critical steps in normal cortical formation and function. Defects in this process can lead to many brain disorders. MicroRNA dysregulation in the dorsolateral prefrontal cortex is associated with risk for a variety of developmental and psychiatric conditions. However, the molecular mechanisms underlying this process remain largely unknown. In this study, we found that microRNA-495-3p (miR-495) is expressed in NPCs of the developing mouse cerebral cortex. Furthermore, aberrant expression of miR-495 promotes the formation of superficial neurons. Our results suggest that miR-495 can target transcription factor 4 (TCF4), a gene linked to the neurodevelopmental disorder Pitt-Hopkins syndrome (PTHS), to ensure normal differentiation of NPCs in the developing cerebral cortex. Furthermore, TCF4 loss-of-function and gain-of-function experiments show opposite effects on miR-495 regulation of neural progenitor differentiation potential. Together, these results demonstrated that miR-495 regulates cortical development through TCF4 for the first time.