Positive feedback between RNA-binding protein HuD and transcription factor SATB1 promotes neurogenesis

Proc Natl Acad Sci U S A. 2015 Sep 8;112(36):E4995-5004. doi: 10.1073/pnas.1513780112. Epub 2015 Aug 24.


The mammalian embryonic lethal abnormal vision (ELAV)-like protein HuD is a neuronal RNA-binding protein implicated in neuronal development, plasticity, and diseases. Although HuD has long been associated with neuronal development, the functions of HuD in neural stem cell differentiation and the underlying mechanisms have gone largely unexplored. Here we show that HuD promotes neuronal differentiation of neural stem/progenitor cells (NSCs) in the adult subventricular zone by stabilizing the mRNA of special adenine-thymine (AT)-rich DNA-binding protein 1 (SATB1), a critical transcriptional regulator in neurodevelopment. We find that SATB1 deficiency impairs the neuronal differentiation of NSCs, whereas SATB1 overexpression rescues the neuronal differentiation phenotypes resulting from HuD deficiency. Interestingly, we also discover that SATB1 is a transcriptional activator of HuD during NSC neuronal differentiation. In addition, we demonstrate that NeuroD1, a neuronal master regulator, is a direct downstream target of SATB1. Therefore, HuD and SATB1 form a positive regulatory loop that enhances NeuroD1 transcription and subsequent neuronal differentiation. Our results here reveal a novel positive feedback network between an RNA-binding protein and a transcription factor that plays critical regulatory roles in neurogenesis.

Keywords: HuD; NeuroD1; SATB1; neural stem cells; neurogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Binding Sites / genetics
  • Blotting, Western
  • Cell Differentiation
  • Cells, Cultured
  • ELAV-Like Protein 4 / genetics
  • ELAV-Like Protein 4 / metabolism*
  • Feedback, Physiological*
  • Lateral Ventricles / cytology
  • Lateral Ventricles / metabolism
  • Male
  • Matrix Attachment Region Binding Proteins / genetics
  • Matrix Attachment Region Binding Proteins / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Molecular Sequence Data
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Neurogenesis*
  • Neurons / cytology
  • Neurons / metabolism
  • Olfactory Bulb / cytology
  • Olfactory Bulb / metabolism
  • Protein Binding
  • RNA Interference
  • RNA Stability
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction


  • Basic Helix-Loop-Helix Transcription Factors
  • ELAV-Like Protein 4
  • Elavl4 protein, mouse
  • Matrix Attachment Region Binding Proteins
  • Neurod1 protein, mouse
  • RNA, Messenger
  • Satb1 protein, mouse