Disruption of neuronal migration by RNAi of Dyx1c1 results in neocortical and hippocampal malformations.
The brains of individuals with developmental dyslexia have neocortical neuronal migration abnormalities including molecular layer heterotopias, laminar dysplasias, and periventricular nodular heterotopias (PNH). RNA interference (RNAi) of Dyx1c1, a candidate dyslexia susceptibility gene, disrupts neuronal migration in developing embryonic neocortex. Using in utero electroporation, we cotransfected cells in the rat neocortical ventricular zone (VZ) at E14/15 with short hairpin RNA vectors targeting Dyx1c1 along with either plasmids encoding enhanced green fluorescent protein or plasmids encoding monomeric red fluorescent protein only. RNAi of Dyx1c1 resulted in pockets of unmigrated neurons resembling PNH. The pattern of migration of transfected neurons was bimodal, with approximately 20% of the neurons migrating a short distance from the VZ and another 40% that migrated past their expected lamina. Approximately 25% of the transfected brains had hippocampal pyramidal cell migration anomalies. Molecular layer ectopias, which were not related to injection site artifacts, were also seen in 25% of the animals. These results support the hypothesis that targeted disruption of the candidate dyslexia susceptibility gene, Dyx1c1, results in neuronal migration disorders similar to those seen in the brains of dyslexics.
Rosen
Glenn D
GD
Dyslexia Research Laboratory and Charles A Dana Research Institute, Department of Neurology, Division of Behavioral Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. grosen@bidmc.harvard.edu
Bai
Jilin
J
Wang
Yu
Y
Fiondella
Christopher G
CG
Threlkeld
Steven W
SW
LoTurco
Joseph J
JJ
Galaburda
Albert M
AM
D000818:Animals; D002465:Cell Movement; D003598:Cytoskeletal Proteins; D020868:Gene Silencing; D006624:Hippocampus / Q000002:abnormalities* / Q000503:physiopathology*; D009024:Morphogenesis; D019579:Neocortex / Q000002:abnormalities* / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D003598:Cytoskeletal Proteins; C478878:DNAAF4 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins