Postnatal analysis of the effect of embryonic knockdown and overexpression of candidate dyslexia susceptibility gene homolog Dcdc2 in the rat

Neuroscience. 2008 Mar 27;152(3):723-33. doi: 10.1016/j.neuroscience.2008.01.020. Epub 2008 Jan 19.

Abstract

Embryonic knockdown of candidate dyslexia susceptibility gene (CDSG) homologs in cerebral cortical progenitor cells in the rat results in acute disturbances of neocortical migration. In the current report we investigated the effects of embryonic knockdown and overexpression of the homolog of DCDC2, one of the CDSGs, on the postnatal organization of the cerebral cortex. Using a within-litter design, we transfected cells in rat embryo neocortical ventricular zone around embryonic day (E) 15 with either 1) small hairpin RNA (shRNA) vectors targeting Dcdc2, 2) a DCDC2 overexpression construct, 3) Dcdc2 shRNA along with DCDC2 overexpression construct, 4) an overexpression construct composed of the C terminal domain of DCDC2, or 5) an overexpression construct composed of the DCX terminal domain of DCDC2. RNAi of Dcdc2 resulted in pockets of heterotopic neurons in the periventricular region. Approximately 25% of the transfected brains had hippocampal pyramidal cell migration anomalies. Dcdc2 shRNA-transfected neurons migrated in a bimodal pattern, with approximately 7% of the neurons migrating a short distance from the ventricular zone, and another 30% migrating past their expected lamina. Rats transfected with Dcdc2 shRNA along with the DCDC2 overexpression construct rescued the periventricular heterotopia phenotype, but did not affect the percentage of transfected neurons that migrate past their expected laminar location. There were no malformations associated with any of the overexpression constructs, nor was there a significant laminar disruption of migration. These results support the claim that knockdown of Dcdc2 expression results in neuronal migration disorders similar to those seen in the brains of dyslexics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Movement / genetics*
  • Cerebral Cortex / abnormalities*
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / physiopathology
  • Choristoma / genetics
  • Choristoma / metabolism
  • Choristoma / physiopathology
  • Doublecortin Protein
  • Down-Regulation / genetics
  • Dyslexia / genetics*
  • Dyslexia / metabolism
  • Dyslexia / physiopathology
  • Gene Expression Regulation, Developmental / genetics
  • Gene Targeting
  • Genetic Predisposition to Disease / genetics*
  • Hippocampus / abnormalities
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • Humans
  • Malformations of Cortical Development, Group II / genetics*
  • Malformations of Cortical Development, Group II / metabolism
  • Malformations of Cortical Development, Group II / physiopathology
  • Microtubule-Associated Proteins / biosynthesis
  • Microtubule-Associated Proteins / deficiency
  • Microtubule-Associated Proteins / genetics*
  • Pyramidal Cells / metabolism
  • Pyramidal Cells / pathology
  • RNA Interference
  • Rats
  • Rats, Wistar
  • Transfection

Substances

  • DCDC2 protein, human
  • Dcx protein, rat
  • Doublecortin Protein
  • Microtubule-Associated Proteins