title: Loss of Emx2 function leads to ectopic expression of Wnt1 in the developing telencephalon and cortical dysplasia.
abstract: Leptomeningeal glioneuronal heterotopias are a focal type of cortical dysplasia in which neural cells migrate aberrantly into superficial layers of the cerebral cortex and meninges. These heterotopias are frequently observed as microscopic abnormalities in the brains of individuals with central nervous system (CNS) malformations and epilepsy. Previous work has demonstrated that the function of Emx2, which encodes a homeodomain transcription factor, is essential for development of the cortical preplate, which gives rise to the marginal zone and subplate. However, transcriptional targets of EMX2 during CNS development are unknown. We report that leptomeningeal glioneuronal heterotopias form in Emx2(-/-) mice that are equivalent to human lesions. Additionally, we observed ectopic expression of Wnt1 in the embryonic roofplate organizer region and dorsal telencephalon. To determine the phenotypic consequences of such Wnt1 misexpression, we deleted a putative EMX2 DNA-binding site from the Wnt1 enhancer and used this to misexpress Wnt1 in the developing murine CNS. Heterotopias were detected in transgenic mice as early as 13.5 days postcoitum, consistent with a defect of preplate development during early phases of radial neuronal migration. Furthermore, we observed diffuse abnormalities of reelin- and calretinin-positive cell populations in the marginal zone and subplate similar to those observed in Emx2-null animals. Taken together, these findings indicate that EMX2 is a direct repressor of Wnt1 expression in the developing mammalian telencephalon. They further suggest that EMX2-Wnt1 interactions are essential for normal development of preplate derivatives in the mammalian cerebral cortex.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, MA 0215, USA.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.forename: Yann
authors.initials: Y
authors.lastname: Echelard
authors.forename: Stavroula
authors.initials: S
authors.lastname: Assimacopoulos
authors.forename: Paul S
authors.initials: PS
authors.lastname: Danielian
authors.forename: Sovann
authors.initials: S
authors.lastname: Kaing
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Grove
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
mesh_terms: D000818:Animals; D001665:Binding Sites; D002828:Choristoma / Q000473:pathology*; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D008578:Meninges / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009457:Neuroglia; D009474:Neurons; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000091042:Reelin Protein; D013687:Telencephalon / Q000254:growth & development*; D014157:Transcription Factors; D019076:Transgenes; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins; D000099260:Empty Spiracles Homeobox Proteins
chemical_list: D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; D000091042:Reelin Protein; D014157:Transcription Factors; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins; D000099260:Empty Spiracles Homeobox Proteins; C495247:WNT1 protein, human; C495246:Wnt1 protein, mouse; C000717127:RELN protein, human; C000717128:Reln protein, mouse