Fragile X-related proteins regulate mammalian circadian behavioral rhythms

Am J Hum Genet. 2008 Jul;83(1):43-52. doi: 10.1016/j.ajhg.2008.06.003. Epub 2008 Jun 26.


Fragile X syndrome results from the absence of the fragile X mental retardation 1 (FMR1) gene product (FMRP). FMR1 has two paralogs in vertebrates: fragile X related gene 1 and 2 (FXR1 and FXR2). Here we show that Fmr1/Fxr2 double knockout (KO) and Fmr1 KO/Fxr2 heterozygous animals exhibit a loss of rhythmic activity in a light:dark (LD) cycle, and that Fmr1 or Fxr2 KO mice display a shorter free-running period of locomotor activity in total darkness (DD). Molecular analysis and in vitro electrophysiological studies suggest essentially normal function of cells in the suprachiasmatic nucleus (SCN) in Fmr1/Fxr2 double KO mice. However, the cyclical patterns of abundance of several core clock component messenger (m) RNAs are altered in the livers of double KO mice. Furthermore, FXR2P alone or FMRP and FXR2P together can increase PER1- or PER2-mediated BMAL1-Neuronal PAS2 (NPAS2) transcriptional activity in a dose-dependent manner. These data collectively demonstrate that FMR1 and FXR2 are required for the presence of rhythmic circadian behavior in mammals and suggest that this role may be relevant to sleep and other behavioral alterations observed in fragile X patients.

Publication types

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

MeSH terms

  • ARNTL Transcription Factors
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Behavior, Animal*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Circadian Rhythm / genetics*
  • Cryptochromes
  • Electrophysiology
  • Flavoproteins / metabolism
  • Fragile X Syndrome
  • Gene Expression Regulation* / genetics
  • Heterozygote
  • In Situ Hybridization
  • Liver / chemistry
  • Male
  • Mammals / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / physiology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Period Circadian Proteins
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics*
  • Suprachiasmatic Nucleus / cytology
  • Suprachiasmatic Nucleus / metabolism
  • Time Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • ARNTL Transcription Factors
  • ARNTL protein, human
  • Arntl protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • Cryptochromes
  • FXR2 protein, mouse
  • Flavoproteins
  • Fxr1h protein, mouse
  • Nerve Tissue Proteins
  • Npas2 protein, mouse
  • Nuclear Proteins
  • PER1 protein, human
  • Per1 protein, mouse
  • Per2 protein, mouse
  • Period Circadian Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Transcription Factors