Necdin downregulates CDC2 expression to attenuate neuronal apoptosis

J Neurosci. 2006 Nov 15;26(46):12003-13. doi: 10.1523/JNEUROSCI.3002-06.2006.


The cell cycle-regulatory transcription factor E2F1 induces apoptosis of postmitotic neurons in developmental and pathological situations. E2F1 transcriptionally activates many proapoptotic genes including the cyclin-dependent protein kinase cell division cycle 2 (Cdc2). Necdin is a potent mitotic suppressor expressed predominantly in postmitotic neurons and interacts with E2F1 to suppress E2F1-mediated gene transcription. The necdin gene NDN is maternally imprinted and expressed only from the paternal allele. Deletion of the paternal NDN is implicated in the pathogenesis of Prader-Willi syndrome, a genomic imprinting-associated neurodevelopmental disorder. Here, we show that paternally expressed necdin represses E2F1-dependent cdc2 gene transcription and attenuates apoptosis of postmitotic neurons. Necdin was abundantly expressed in differentiated cerebellar granule neurons (CGNs). Neuronal activity deprivation elevated the expression of both E2F1 and Cdc2 in primary CGNs prepared from mice at postnatal day 6, whereas the necdin levels remained unchanged. In chromatin immunoprecipitation analysis, endogenous necdin was associated with the cdc2 promoter containing an E2F-binding site in activity-deprived CGNs. After activity deprivation, CGNs underwent apoptosis, which was augmented in those prepared from mice defective in the paternal Ndn allele (Ndn(+m/-p)). The levels of cdc2 mRNA, protein, and kinase activity were significantly higher in Ndn(+m/-p) CGNs than in wild-type CGNs under activity-deprived conditions. Furthermore, the populations of Cdc2-immunoreactive and apoptotic cells were increased in the cerebellum in vivo of Ndn(+m/-p) mice. These results suggest that endogenous necdin attenuates neuronal apoptosis by suppressing the E2F1-Cdc2 system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / genetics*
  • Binding Sites / genetics
  • CDC2 Protein Kinase / biosynthesis*
  • CDC2 Protein Kinase / genetics
  • Cell Count
  • Cells, Cultured
  • Cerebellar Cortex / cytology
  • Cerebellar Cortex / growth & development
  • Cerebellar Cortex / metabolism*
  • Down-Regulation / physiology*
  • E2F1 Transcription Factor / metabolism
  • Gene Expression Regulation, Developmental / physiology
  • Mice
  • Mice, Inbred ICR
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / cytology
  • Neurons / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / metabolism
  • Regulatory Elements, Transcriptional / genetics


  • E2F1 Transcription Factor
  • E2f1 protein, mouse
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • RNA, Messenger
  • necdin
  • CDC2 Protein Kinase