NEUROG2 drives cell cycle exit of neuronal precursors by specifically repressing a subset of cyclins acting at the G1 and S phases of the cell cycle

Mol Cell Biol. 2012 Jul;32(13):2596-607. doi: 10.1128/MCB.06745-11. Epub 2012 Apr 30.


Proneural NEUROG2 (neurogenin 2 [Ngn2]) is essential for neuronal commitment, cell cycle withdrawal, and neuronal differentiation. Although NEUROG2's influence on neuronal commitment and differentiation is beginning to be clarified, its role in cell cycle withdrawal remains unknown. We therefore set out to investigate the molecular mechanisms by which NEUROG2 induces cell cycle arrest during spinal neurogenesis. We developed a large-scale chicken embryo strategy, designed to find gene networks modified at the onset of NEUROG2 expression, and thereby we identified those involved in controlling the cell cycle. NEUROG2 activation leads to a rapid decrease of a subset of cell cycle regulators acting at G(1) and S phases, including CCND1, CCNE1/2, and CCNA2 but not CCND2. The use of NEUROG2VP16 and NEUROG2EnR, acting as the constitutive activator and repressor, respectively, indicates that NEUROG2 indirectly represses CCND1 and CCNE2 but opens the possibility that CCNE2 is also repressed by a direct mechanism. We demonstrated by phenotypic analysis that this rapid repression of cyclins prevents S phase entry of neuronal precursors, thus favoring cell cycle exit. We also showed that cell cycle exit can be uncoupled from neuronal differentiation and that during normal development NEUROG2 is in charge of tightly coordinating these two processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Avian Proteins / antagonists & inhibitors
  • Avian Proteins / genetics
  • Avian Proteins / metabolism*
  • Base Sequence
  • Cell Cycle Checkpoints / genetics
  • Cell Cycle Checkpoints / physiology*
  • Cell Proliferation
  • Chick Embryo
  • Cyclin A2 / genetics
  • Cyclin A2 / metabolism
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Cyclin E / genetics
  • Cyclin E / metabolism
  • Cyclins / genetics
  • Cyclins / metabolism*
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • G1 Phase
  • Gene Expression Regulation, Developmental
  • Gene Regulatory Networks
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / metabolism*
  • Neurogenesis / genetics
  • Neurogenesis / physiology
  • RNA, Small Interfering / genetics
  • S Phase


  • Avian Proteins
  • Cyclin A2
  • Cyclin E
  • Cyclins
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • Cyclin D1