Aberrant differentiation of glutamatergic cells in neocortex of mouse model for fragile X syndrome

Neurobiol Dis. 2009 Feb;33(2):250-9. doi: 10.1016/j.nbd.2008.10.010. Epub 2008 Nov 6.

Abstract

The lack of fragile X mental retardation protein (FMRP) causes fragile X syndrome, a common form of inherited mental retardation. Our previous studies revealed alterations in the differentiation of FMRP-deficient neural progenitors. Here, we show abnormalities in neurogenesis in the mouse and human embryonic FMRP-deficient brain as well as after in utero transfection of I304N mutated FMRP, which acts in a dominant negative manner in the wild-type mouse brain. Progenitors accumulated abnormally in the subventricular zone of the embryonic Fmr1-knockout (Fmr1-KO) mouse neocortex. An increased density of cells expressing sequentially an intermediate progenitor marker, T-box transcription factor (Tbr2), and a postmitotic neuron marker, T-brain 1 (Tbr1), indicated that the differentiation to glutamatergic cell lineages was particularly disturbed. These abnormalities were associated with an increased density of pyramidal cells of the layer V in the early postnatal neocortex suggesting a role for FMRP in the regulation of the differentiation of neocortical glutamatergic neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cell Differentiation
  • Cell Lineage
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Excitatory Amino Acid Transporter 1 / metabolism
  • Fatty Acid-Binding Protein 7
  • Fatty Acid-Binding Proteins / metabolism
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Mental Retardation Protein / physiology
  • Fragile X Syndrome / embryology
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / pathology
  • Fragile X Syndrome / physiopathology*
  • Glutamic Acid / metabolism*
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Knockout
  • Mutation
  • Neocortex / embryology*
  • Neocortex / pathology
  • Neocortex / physiopathology
  • Nerve Tissue Proteins / metabolism
  • Neurogenesis*
  • Neurons / cytology
  • Neurons / metabolism*
  • Pyramidal Cells / growth & development
  • Stem Cells / cytology*
  • T-Box Domain Proteins / metabolism

Substances

  • DNA-Binding Proteins
  • Eomes protein, mouse
  • Excitatory Amino Acid Transporter 1
  • FMR1 protein, human
  • Fabp7 protein, mouse
  • Fatty Acid-Binding Protein 7
  • Fatty Acid-Binding Proteins
  • Fmr1 protein, mouse
  • Nerve Tissue Proteins
  • Slc1a3 protein, mouse
  • T-Box Domain Proteins
  • Tbr1 protein, mouse
  • Fragile X Mental Retardation Protein
  • Glutamic Acid