Disruption of CREB function in brain leads to neurodegeneration

Nat Genet. 2002 May;31(1):47-54. doi: 10.1038/ng882. Epub 2002 Apr 22.


Control of cellular survival and proliferation is dependent on extracellular signals and is a prerequisite for ordered tissue development and maintenance. Activation of the cAMP responsive element binding protein (CREB) by phosphorylation has been implicated in the survival of mammalian cells. To define its roles in the mouse central nervous system, we disrupted Creb1 in brain of developing and adult mice using the Cre/loxP system. Mice with a Crem(-/-) background and lacking Creb in the central nervous system during development show extensive apoptosis of postmitotic neurons. By contrast, mice in which both Creb1 and Crem are disrupted in the postnatal forebrain show progressive neurodegeneration in the hippocampus and in the dorsolateral striatum. The striatal phenotype is reminiscent of Huntington disease and is consistent with the postulated role of CREB-mediated signaling in polyglutamine-triggered diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Brain / physiology*
  • Corpus Striatum / pathology
  • Cyclic AMP Response Element Modulator
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology
  • Female
  • Humans
  • Huntington Disease / etiology
  • Huntington Disease / genetics
  • Huntington Disease / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Nerve Degeneration / etiology*
  • Nerve Degeneration / genetics
  • Nerve Degeneration / pathology
  • Peptides / genetics
  • Phenotype
  • Repressor Proteins*
  • Signal Transduction
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / physiology*


  • CREB1 protein, human
  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Peptides
  • Repressor Proteins
  • Transcription Factors
  • Cyclic AMP Response Element Modulator
  • polyglutamine