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

  • Stem Cell Reports. 2026 Jun 9;21(6):102927. doi: 10.1016/j.stemcr.2026.102927.
Xinrun Wang  1 ,  Li Li  2 ,  Zhuo Chen  1 ,  Yi Zeng  1 ,  Pengcheng Shu  1 ,  Lin Hou  1 ,  Bin Yin  1 ,  Wei Liu  3 ,  Xiaozhong Peng  4
Affiliations
  • 1. State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry & Molecular Biology, Medical Primate Research Center, Neuroscience Center, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
  • 2. State Key Laboratory of Respiratory Health and Multimorbidity, National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Sciences, CAMS & PUMC, Beijing 100021, China.
  • 3. State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry & Molecular Biology, Medical Primate Research Center, Neuroscience Center, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry & Molecular Biology, Medical Primate Research Center, Neuroscience Center, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; State Key Laboratory of Respiratory Health and Multimorbidity, National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Sciences, CAMS & PUMC, Beijing 100021, China. Electronic address: [email protected].
PMID: 42167224 DOI: 10.1016/j.stemcr.2026.102927
Abstract

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.

Keywords
APH1A; miR-151-5p; neocortical development; neural stem cells; notch signaling.
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