Overexpression of Down syndrome cell adhesion molecule impairs precise synaptic targeting

Nat Neurosci. 2013 Jun;16(6):677-82. doi: 10.1038/nn.3396. Epub 2013 May 12.

Abstract

Fragile X syndrome is caused by the loss of Fragile X mental retardation protein (FMRP), an RNA-binding protein that suppresses protein translation. We found that FMRP binds to Down syndrome cell adhesion molecule (Dscam) RNA, a molecule that is involved in neural development and has been implicated in Down syndrome. Elevated Dscam protein levels in FMRP null Drosophila and in flies with three copies of the Dscam gene both produced specific and similar synaptic targeting errors in a hard-wired neural circuit, which impaired the flies' sensory perception. Reducing Dscam levels in FMRP null flies reduced synaptic targeting errors and rescued behavioral responses. Our results indicate that excess Dscam protein may be a common molecular mechanism underlying altered neural wiring in intellectual disabilities such as Fragile X and Down syndromes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • Brain / metabolism*
  • Brain / physiopathology
  • Cell Adhesion Molecules / biosynthesis
  • Cell Adhesion Molecules / genetics*
  • Down Syndrome / genetics*
  • Down Syndrome / metabolism
  • Down Syndrome / physiopathology*
  • Drosophila Proteins / biosynthesis
  • Drosophila Proteins / genetics*
  • Drosophila melanogaster
  • Fragile X Mental Retardation Protein / genetics
  • Gene Expression Regulation* / genetics
  • Neurons / metabolism*
  • Neurons / pathology
  • Synapses / genetics*
  • Synapses / metabolism

Substances

  • Cell Adhesion Molecules
  • Drosophila Proteins
  • Dscam1 protein, Drosophila
  • Fragile X Mental Retardation Protein