title: Dorsal telencephalon-specific RA-GEF-1 knockout mice develop heterotopic cortical mass and commissural fiber defect.
abstract: Neural migration defects lead to various types of human malformations of cortical development including subcortical band heterotopia, which shows formation of a secondary cortical plate beneath the primary cortex and is typically caused by mutation of the DCX (doublecortin) gene. Subcortical band heterotopia is usually associated with mental retardation and epilepsy. We previously discovered RA-GEF-1 as a guanine nucleotide exchange factor (GEF) for Rap1 small GTPase. Here we have analysed its in-vivo role in formation of the adult cerebral cortex by using telencephalon-specific RA-GEF-1 conditional knockout (cKO) mice, generated by mating RA-GEF-1(flox/flox) mice with Emx1-cre knockin mice. RA-GEF-1 cKO mice showed severe defects in their brain structures including an ectopic cortical mass underlying a relatively normal cortex. The ectopic cortical mass lacked the normal six-layered lamination but preserved the subcortical connectivity as revealed by retrograde tracing. Further, RA-GEF-1 cKO mice exhibited a lower threshold for the induction of epileptic seizures. These phenotypes have a resemblance to those of human subcortical band heterotopia. In addition, the agenesis of anterior commissures, the dorsal hippocampus commissure, the corpus callosum and the enlargement of the lateral ventricles were observed in cKO mice. Our findings suggest a crucial function of RA-GEF-1 in neural migration.
authors.affiliation: Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Shymaa E
authors.initials: SE
authors.lastname: Bilasy
authors.forename: Takaya
authors.initials: T
authors.lastname: Satoh
authors.forename: Shuji
authors.initials: S
authors.lastname: Ueda
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
authors.forename: Hoshimi
authors.initials: H
authors.lastname: Kanemura
authors.forename: Atsu
authors.initials: A
authors.lastname: Aiba
authors.forename: Toshio
authors.initials: T
authors.lastname: Terashima
authors.forename: Tohru
authors.initials: T
authors.lastname: Kataoka
mesh_terms: D061085:Agenesis of Corpus Callosum; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000235:genetics*; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000254:growth & development / Q000473:pathology; D003337:Corpus Callosum / Q000254:growth & development / Q000473:pathology; D000089662:Doublecortin Protein; D005455:Fluorescent Antibody Technique; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012640:Seizures / Q000235:genetics
chemical_list: C508086:CNrasGEF protein, mouse; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D020662:Guanine Nucleotide Exchange Factors