Abstract
Developmental dyslexia is a language learning disorder that affects approximately 4–10% of the population. A number of candidate dyslexia susceptibility genes have been identified, including DCDC2 and KIAA0319 on Chromosome (Chr) 6p22.2 and DYX1C1 on Chr 15q21. Embryonic knockdown of the function of homologs of these genes in rat neocortical projection cell progenitors by in utero electroporation of plasmids encoding small hairpin RNA (shRNA) revealed that all three genes disrupted neuronal migration to the neocortex. Specifically, this disruption would result in heterotopia formation (Dyx1c1 and Kiaa0319) and/or overmigration past their expected laminar location (Dyx1c1 and Dcdc2). In these experiments, neurons normally destined for the upper neocortical laminæ were transfected on embryonic day (E) 15.5, and we designed experiments to test whether these migration phenotypes were the result of targeting a specific type of projection neuron. We transfected litters with Dcdc2 shRNA, Dyx1c1 shRNA, Kiaa0319 shRNA, or fluorescent protein (as a control) at each of three gestational ages (E14.5, E15.5, or E16.5). Pups were allowed to come to term, and their brains were examined at 3 weeks of age for the position of transfected cells. We found that age of transfection did not affect the percentage of unmigrated neurons—transfection with Kiaa0319 shRNA resulted in heterotopia formation at all three ages. Overmigration of neurons transfected with Dcdc2 shRNA, while present following transfections at the later ages, did not occur following E14.5 transfections. These results are considered in light of the known functions of each of these candidate dyslexia susceptibility genes.
Highlights
Developmental dyslexia, a language learning disorder, affects approximately 4–10% of the global population and has a strong genetic component
None of the 5 rats embryonically transfected with Dcdc2 small hairpin RNA (shRNA) and 1/7 rats transfected with Dyx1c1 shRNA had heterotopias
Previous research demonstrated that embryonic knockdown of candidate dyslexia susceptibility gene (CDSG) homologs at E15.5 results in disruption of neuronal migration, including white matter heterotopias and/or migration of transfected neurons past their expected laminar location in the neocortex
Summary
Developmental dyslexia, a language learning disorder, affects approximately 4–10% of the global population and has a strong genetic component. Delineating the specific functions of these genes has been a target of intense investigation in recent years These three CDSGs have been shown to be involved in neocortical neuronal migration [2,23,24,25,26,27,28,29,30,31,32]. Only heterotopias were seen following identical transfection with plasmids encoding Kiaa0319 shRNA [30], whereas knockdown of Dcdc by the same method resulted in the overmigration phenotype only [24] In these experiments, neurons normally destined for the upper neocortical laminæ were transfected, which raises a number of questions: Are the migration phenotypes the result of targeting a specific type of projection neuron? We found that age of transfection did not affect the percentage of unmigrated neurons, but did influence the overmigration phenotype
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