Pathophysiological analyses of cortical malformation using gyrencephalic mammals

• Published in: Scientific reports 2015-10, Vol.5 (1), p.15370-15370, Article 15370
• Main Authors: Masuda, Kosuke, Toda, Tomohisa, Shinmyo, Yohei, Ebisu, Haruka, Hoshiba, Yoshio, Wakimoto, Mayu, Ichikawa, Yoshie, Kawasaki, Hiroshi
• Format: Article
• Language: English
• Subjects: 13; 42/100; 42/109; 42/44; 631/378/2571; 692/617/375/366; Animals; Astrocytes - metabolism; Biomarkers; Cell Proliferation; Cerebral cortex; Cerebral Cortex - embryology; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Disease Models, Animal; Dysplasia; Electroporation; Eye Proteins - metabolism; Ferrets; Fibroblast growth factor 8; Fibroblast Growth Factor 8 - genetics; Fibroblast Growth Factor 8 - metabolism; Glial cells; Homeodomain Proteins - metabolism; Humanities and Social Sciences; Malformations of Cortical Development - etiology; Malformations of Cortical Development - pathology; Mammals; Megalencephaly; Mice; Molecular modelling; multidisciplinary; Neural Stem Cells - metabolism; Oligodendroglia - metabolism; Paired Box Transcription Factors - metabolism; PAX6 Transcription Factor; Phenotype; Polymicrogyria; Radial glial cells; Repressor Proteins - metabolism; Rodents; Science; Stem cells; T-Box Domain Proteins - metabolism; Thanatophoric Dysplasia - etiology; Thanatophoric Dysplasia - pathology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep15370

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.