miR-151-5p regulates neural stem cell fate by targeting APH1A to modulate Notch signaling gradients

The precise regulation of neural stem cell (NSC) fate is fundamental to neocortical development. MicroRNAs (miRNAs) are critical post-transcriptional regulators in this process, yet the functions of many remain unknown. Here, we found miR-151-5p is expressed in NSCs of the developing mouse cerebral cortex. Conditional knockout of miR-151-5p increased SOX2 expression in NSCs and enhanced their proliferative capacity. Mechanistically, we identified APH1A, a core subunit of the γ-secretase complex, as a direct target of miR-151-5p. Notably, overexpression of APH1A phenocopied the effects of miR-151-5p knockout, promoting NSC proliferation by elevating NICD levels. These findings demonstrate that miR-151-5p biases NSC fate specification by targeting APH1A to modulate the Notch signaling pathway, thereby fine-tuning the balance between NSC maintenance and differentiation. In summary, our study unveils a novel miR-151-5p/APH1A/Notch signaling axis that governs NSC fate, adding a critical layer of post-transcriptional regulation to our understanding of mammalian neocortical development.