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RNA-binding protein Sam68 controls synapse number and local β-actin mRNA metabolism in dendrites.

Proper synaptic function requires the spatial and temporal compartmentalization of RNA metabolism via transacting RNA-binding proteins (RBPs). Loss of RBP activity leads to abnormal posttranscriptional regulation and results in diverse neurological disorders with underlying deficits in synaptic morphology and transmission. Functional loss of the 68-kDa RBP Src associated in mitosis (Sam68) is associated with the pathogenesis of the neurological disorder fragile X tremor/ataxia syndrome. Sam68 binds to the mRNA of β-actin (actb), an integral cytoskeletal component of dendritic spines. We show that Sam68 knockdown or disruption of the binding between Sam68 and its actb mRNA cargo in primary hippocampal cultures decreases the amount of actb mRNA in the synaptodendritic compartment and results in fewer dendritic spines. Consistent with these observations, we find that Sam68-KO mice have reduced levels of actb mRNA associated with synaptic polysomes and diminished levels of synaptic actb protein, suggesting that Sam68 promotes the translation of actb mRNA at synapses in vivo. Moreover, genetic knockout of Sam68 or acute knockdown in vivo results in fewer excitatory synapses in the hippocampal formation as assessed morphologically and functionally. Therefore, we propose that Sam68 regulates synapse number in a cell-autonomous manner through control of postsynaptic actb mRNA metabolism. Our research identifies a role for Sam68 in synaptodendritic posttranscriptional regulation of actb and may provide insight into the pathophysiology of fragile X tremor/ataxia syndrome.

Pubmed ID: 23382180 RIS Download

Mesh terms: Actins | Adaptor Proteins, Signal Transducing | Animals | Dendrites | Mice | Mice, Knockout | RNA, Messenger | RNA-Binding Proteins | Rats | Rats, Sprague-Dawley | Synapses

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Associated grants

  • Agency: NIDA NIH HHS, Id: R01 DA017392
  • Agency: NINDS NIH HHS, Id: F31-NS073200
  • Agency: NIA NIH HHS, Id: R01 AG039521
  • Agency: NINDS NIH HHS, Id: F31 NS073200
  • Agency: NIMH NIH HHS, Id: R01 MH081935
  • Agency: NIMH NIH HHS, Id: R01-MH081935
  • Agency: NIDA NIH HHS, Id: R01-DA17392
  • Agency: NIGMS NIH HHS, Id: T32 GM007288
  • Agency: NIMH NIH HHS, Id: K01 MH073759
  • Agency: NIMH NIH HHS, Id: K01-MH073759
  • Agency: NIA NIH HHS, Id: R01-AG039521

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