APP intracellular domain acts as a transcriptional regulator of miR-663 suppressing neuronal differentiation

Cell Death Dis. 2015 Feb 19;6(2):e1651. doi: 10.1038/cddis.2015.10.

Abstract

Amyloid precursor protein (APP) is best known for its involvement in the pathogenesis of Alzheimer's disease. We have previously demonstrated that APP intracellular domain (AICD) regulates neurogenesis; however, the mechanisms underlying AICD-mediated regulation of neuronal differentiation are not yet fully characterized. Using genome-wide chromatin immunoprecipitation approaches, we found that AICD is specifically recruited to the regulatory regions of several microRNA genes, and acts as a transcriptional regulator for miR-663, miR-3648 and miR-3687 in human neural stem cells. Functional assays show that AICD negatively modulates neuronal differentiation through miR-663, a primate-specific microRNA. Microarray data further demonstrate that miR-663 suppresses the expression of multiple genes implicated in neurogenesis, including FBXL18 and CDK6. Our results indicate that AICD has a novel role in suppression of neuronal differentiation via transcriptional regulation of miR-663 in human neural stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Cell Differentiation / genetics*
  • Cell Differentiation / physiology
  • Cell Line
  • Chromatin Immunoprecipitation
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neurons / cytology*
  • Neurons / metabolism*
  • Protein Binding

Substances

  • Amyloid beta-Protein Precursor
  • DNA-Binding Proteins
  • MIRN663 microRNA, human
  • MicroRNAs