Pathophysiological analyses of cortical malformation using gyrencephalic mammals

Sci Rep. 2015 Oct 20:5:15370. doi: 10.1038/srep15370.

Abstract

One of the most prominent features of the cerebral cortex of higher mammals is the presence of gyri. Because malformations of the cortical gyri are associated with severe disability in brain function, the mechanisms underlying malformations of the cortical gyri have been of great interest. Combining gyrencephalic carnivore ferrets and genetic manipulations using in utero electroporation, here we successfully recapitulated the cortical phenotypes of thanatophoric dysplasia (TD) by expressing fibroblast growth factor 8 in the ferret cerebral cortex. Strikingly, in contrast to TD mice, our TD ferret model showed not only megalencephaly but also polymicrogyria. We further uncovered that outer radial glial cells (oRGs) and intermediate progenitor cells (IPs) were markedly increased. Because it has been proposed that increased oRGs and/or IPs resulted in the appearance of cortical gyri during evolution, it seemed possible that increased oRGs and IPs underlie the pathogenesis of polymicrogyria. Our findings should help shed light on the molecular mechanisms underlying the formation and malformation of cortical gyri in higher mammals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism
  • Biomarkers
  • Cell Proliferation
  • Cerebral Cortex / embryology
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Disease Models, Animal
  • Eye Proteins / metabolism
  • Ferrets
  • Fibroblast Growth Factor 8 / genetics
  • Fibroblast Growth Factor 8 / metabolism
  • Homeodomain Proteins / metabolism
  • Malformations of Cortical Development / etiology*
  • Malformations of Cortical Development / pathology
  • Mice
  • Neural Stem Cells / metabolism
  • Oligodendroglia / metabolism
  • PAX6 Transcription Factor
  • Paired Box Transcription Factors / metabolism
  • Phenotype
  • Repressor Proteins / metabolism
  • T-Box Domain Proteins / metabolism
  • Thanatophoric Dysplasia / etiology
  • Thanatophoric Dysplasia / pathology

Substances

  • Biomarkers
  • Eomes protein, mouse
  • Eye Proteins
  • Homeodomain Proteins
  • PAX6 Transcription Factor
  • Paired Box Transcription Factors
  • Pax6 protein, mouse
  • Repressor Proteins
  • T-Box Domain Proteins
  • Fibroblast Growth Factor 8