title: Embryonic disruption of the candidate dyslexia susceptibility gene homolog Kiaa0319-like results in neuronal migration disorders.
abstract: Developmental dyslexia, the most common childhood learning disorder, is highly heritable, and recent studies have identified KIAA0319-Like (KIAA0319L) as a candidate dyslexia susceptibility gene at the 1p36-34 (DYX8) locus. In this experiment, we investigated the anatomical effects of knocking down this gene during rat corticogenesis. Cortical progenitor cells were transfected using in utero electroporation on embryonic day (E) 15.5 with plasmids encoding either: (1) Kiaa0319l small hairpin RNA (shRNA), (2) an expression construct for human KIAA0319L, (3) Kiaa0319l shRNA+KIAA0319L expression construct (rescue), or (4) controls (scrambled Kiaa0319l shRNA or empty expression vector). Mothers were injected with 5-bromo-2-deoxyuridine (BrdU) at either E13.5, E15.5, or E17.5. Disruption of Kiaa0319l function (by knockdown, overexpression, or rescue) resulted in the formation of large nodular periventricular heterotopia in approximately 25% of the rats, which can be seen as early as postnatal day 1. Only a small subset of heterotopic neurons had been transfected, indicating non-cell autonomous effects of the transfection. Most heterotopic neurons were generated in mid- to late-gestation, and laminar markers suggest that they were destined for upper cortical laminae. Finally, we found that transfected neurons in the cerebral cortex were located in their expected laminae. These results indicate that KIAA0319L is the fourth of four candidate dyslexia susceptibility genes that is involved in neuronal migration, which supports the association of abnormal neuronal migration with developmental dyslexia.
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Platt
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: W T
authors.initials: WT
authors.lastname: Adler
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Mehlhorn
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: G C
authors.initials: GC
authors.lastname: Johnson
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Wright
authors.affiliation: School of Biomedical Sciences & School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: R T
authors.initials: RT
authors.lastname: Choi
authors.affiliation: School of Biomedical Sciences & School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: W H
authors.initials: WH
authors.lastname: Tsang
authors.affiliation: School of Biomedical Sciences & School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: M W
authors.initials: MW
authors.lastname: Poon
authors.affiliation: School of Biomedical Sciences & School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: S Y
authors.initials: SY
authors.lastname: Yeung
authors.affiliation: School of Biomedical Sciences & School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: M M Y
authors.initials: MM
authors.lastname: Waye
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Galaburda
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Electronic address: grosen@bidmc.harvard.edu.
authors.forename: G D
authors.initials: GD
authors.lastname: Rosen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000254:growth & development*; D004198:Disease Susceptibility; D004410:Dyslexia / Q000235:genetics*; D018274:Electroporation; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D054081:Malformations of Cortical Development, Group II / Q000235:genetics*; D058953:Neural Stem Cells / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D055647:Rats, Transgenic; D011956:Receptors, Cell Surface; D014162:Transfection
chemical_list: C541251:KIAA0319L protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface
keywords: RNAi; cerebral cortex; developmental dyslexia; in utero electroporation; neuronal migration