The effects of embryonic knockdown of the candidate dyslexia susceptibility gene homologue Dyx1c1 on the distribution of GABAergic neurons in the cerebral cortex

Abstract Developmental dyslexia is a language-based learning disability, and a number of candidate dyslexia susceptibility genes have been identified, including DYX1C1 , KIAA0319 , and DCDC2 . Knockdown of function by embryonic transfection of small hairpin RNA (shRNA) of rat homologues of these gen...

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Published in:	Neuroscience Vol. 172; no. 1; pp. 535 - 546
Main Authors:	Currier, T.A, Etchegaray, M.A, Haight, J.L, Galaburda, A.M, Rosen, G.D
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Ltd 13-01-2011 Elsevier
Subjects:	Animals Animals, Newborn Biological and medical sciences Carrier Proteins - antagonists & inhibitors Carrier Proteins - genetics cerebral cortex Cerebral Cortex - abnormalities Cerebral Cortex - growth & development Cerebral Cortex - metabolism developmental dyslexia Down-Regulation - genetics DYX1C1 Fundamental and applied biological sciences. Psychology GABA gamma-Aminobutyric Acid - metabolism genetics heterotopia Neurology Neurons - cytology Neurons - metabolism Rats Rats, Wistar RNA Interference - physiology RNA, Small Interfering - genetics Transfection - methods Vertebrates: nervous system and sense organs heterotopia subventricular zone eGFP ventricular zone DYX1C1 VZ PV neuropeptide Y developmental dyslexia small hairpin RNA CR cerebral cortex genetics enhanced green fluorescent protein shRNA ganglionic eminence NPY parvalbumin SVZ GABA calretinin monomeric red fluorescent protein mRFP GE Cerebral cortex Embryo Central nervous system Encephalon Sensitivity Distribution Neurotransmitter Development Gabaergic neuron
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Summary:	Abstract Developmental dyslexia is a language-based learning disability, and a number of candidate dyslexia susceptibility genes have been identified, including DYX1C1 , KIAA0319 , and DCDC2 . Knockdown of function by embryonic transfection of small hairpin RNA (shRNA) of rat homologues of these genes dramatically disrupts neuronal migration to the cerebral cortex by both cell autonomous and non-cell autonomous effects. Here we sought to investigate the extent of non-cell autonomous effects following in utero disruption of the candidate dyslexia susceptibility gene homolog Dyx1c1 by assessing the effects of this disruption on GABAergic neurons. We transfected the ventricular zone of embryonic day (E) 15.5 rat pups with either Dyx1c1 shRNA, DYX1C1 expression construct, both Dyx1c1 shRNA and DYX1C1 expression construct, or a scrambled version of Dyx1c1 shRNA, and sacrificed them at postnatal day 21. The mothers of these rats were injected with BrdU at either E13.5, E15.5, or E17.5. Neurons transfected with Dyx1c1 shRNA were bi-modally distributed in the cerebral cortex with one population in heterotopic locations at the white matter border and another migrating beyond their expected location in the cerebral cortex. In contrast, there was no disruption of migration following transfection with the DYX1C1 expression construct. We found untransfected GABAergic neurons (parvalbumin, calretinin, and neuropeptide Y) in the heterotopic collections of neurons in Dyx1c1 shRNA treated animals, supporting the hypothesis of non-cell autonomous effects. In contrast, we found no evidence that the position of the GABAergic neurons that made it to the cerebral cortex was disrupted by the embryonic transfection with any of the constructs. Taken together, these results support the notion that neurons within heterotopias caused by transfection with Dyx1c1 shRNA result from both cell autonomous and non-cell autonomous effects, but there is no evidence to support non-cell autonomous disruption of neuronal position in the cerebral cortex itself.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 These authors contributed equally to this work.
ISSN:	0306-4522 1873-7544
DOI:	10.1016/j.neuroscience.2010.11.002