A forward genetic screen in mice identifies mutants with abnormal cortical patterning

Cereb Cortex. 2015 Jan;25(1):167-79. doi: 10.1093/cercor/bht209. Epub 2013 Aug 22.

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.

Keywords: ENU mutagenesis; cerebral cortex; cortical lamination; corticofugal axon; reelin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Axons / drug effects
  • Axons / pathology
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cerebral Cortex / abnormalities*
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / pathology*
  • Ethylnitrosourea / toxicity*
  • Extracellular Matrix Proteins / genetics
  • Female
  • Gene Expression Regulation, Developmental / drug effects
  • Genetic Testing / methods*
  • Hydrocephalus / genetics
  • Hydrocephalus / pathology
  • Low Density Lipoprotein Receptor-Related Protein-2 / genetics
  • Male
  • Malformations of Cortical Development / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mutagens / toxicity*
  • Mutation*
  • Nerve Tissue Proteins / genetics
  • Serine Endopeptidases / genetics

Substances

  • Cell Adhesion Molecules, Neuronal
  • Extracellular Matrix Proteins
  • Low Density Lipoprotein Receptor-Related Protein-2
  • Lrp2 protein, mouse
  • Mutagens
  • Nerve Tissue Proteins
  • Serine Endopeptidases
  • reelin protein
  • Ethylnitrosourea