title: A forward genetic screen in mice identifies mutants with abnormal cortical patterning.
abstract: Formation of a 6-layered cortical plate and axon tract patterning are key features of cerebral cortex development. Abnormalities of these processes may be the underlying cause for a range of functional disabilities seen in human neurodevelopmental disorders. To identify mouse mutants with defects in cortical lamination or corticofugal axon guidance, N-ethyl-N-nitrosourea (ENU) mutagenesis was performed using mice expressing LacZ reporter genes in layers II/III and V of the cortex (Rgs4-lacZ) or in corticofugal axons (TAG1-tau-lacZ). Four lines with abnormal cortical lamination have been identified. One of these was a splice site mutation in reelin (Reln) that results in a premature stop codon and the truncation of the C-terminal region (CTR) domain of reelin. Interestingly, this novel allele of Reln did not display cerebellar malformation or ataxia, and this is the first report of a Reln mutant without a cerebellar defect. Four lines with abnormal cortical axon development were also identified, one of which was found by whole-genome resequencing to carry a mutation in Lrp2. These findings demonstrated that the application of ENU mutagenesis to mice carrying transgenic reporters marking cortical anatomy is a sensitive and specific method to identify mutations that disrupt patterning of the developing brain.
authors: Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, University of Washington School of Medicine, Seattle, WA 98101, USA.
authors: Seungshin
authors: S
authors: Ha
authors: Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA Divisions of Human Genetics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA and.
authors: Rolf W
authors: RW
authors: Stottmann
authors: Department of Biomedical Science, The University of Sheffield, Western Bank, Sheffield S10 2TN, UK.
authors: Andrew J
authors: AJ
authors: Furley
authors: Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, University of Washington School of Medicine, Seattle, WA 98101, USA.
authors: David R
authors: DR
authors: Beier
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000187:drug effects / Q000473:pathology*; D005038:Ethylnitrosourea / Q000633:toxicity*; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005820:Genetic Testing / Q000379:methods*; D006849:Hydrocephalus / Q000235:genetics / Q000473:pathology; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics; D008297:Male; D054220:Malformations of Cortical Development / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse; D009153:Mutagens; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D005038:Ethylnitrosourea
keywords: ENU mutagenesis; cerebral cortex; cortical lamination; corticofugal axon; reelin
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