Pathophysiological analyses of cortical malformation using gyrencephalic mammals.
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.
Department of Biophysical Genetics, Graduate School of Medical Sciences, Kanazawa University, Ishikawa 920-8640, Japan.|Brain/Liver Interface Medicine Research Center, Kanazawa University, Ishikawa 920-8640, Japan.|Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Kosuke
K
Masuda
Department of Biophysical Genetics, Graduate School of Medical Sciences, Kanazawa University, Ishikawa 920-8640, Japan.|Brain/Liver Interface Medicine Research Center, Kanazawa University, Ishikawa 920-8640, Japan.|Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Tomohisa
T
Toda
Department of Biophysical Genetics, Graduate School of Medical Sciences, Kanazawa University, Ishikawa 920-8640, Japan.|Brain/Liver Interface Medicine Research Center, Kanazawa University, Ishikawa 920-8640, Japan.
Yohei
Y
Shinmyo
Department of Biophysical Genetics, Graduate School of Medical Sciences, Kanazawa University, Ishikawa 920-8640, Japan.|Brain/Liver Interface Medicine Research Center, Kanazawa University, Ishikawa 920-8640, Japan.|Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Haruka
H
Ebisu
Department of Biophysical Genetics, Graduate School of Medical Sciences, Kanazawa University, Ishikawa 920-8640, Japan.|Brain/Liver Interface Medicine Research Center, Kanazawa University, Ishikawa 920-8640, Japan.|Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Yoshio
Y
Hoshiba
Department of Biophysical Genetics, Graduate School of Medical Sciences, Kanazawa University, Ishikawa 920-8640, Japan.|Brain/Liver Interface Medicine Research Center, Kanazawa University, Ishikawa 920-8640, Japan.|Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Mayu
M
Wakimoto
Department of Biophysical Genetics, Graduate School of Medical Sciences, Kanazawa University, Ishikawa 920-8640, Japan.|Brain/Liver Interface Medicine Research Center, Kanazawa University, Ishikawa 920-8640, Japan.
Yoshie
Y
Ichikawa
Department of Biophysical Genetics, Graduate School of Medical Sciences, Kanazawa University, Ishikawa 920-8640, Japan.|Brain/Liver Interface Medicine Research Center, Kanazawa University, Ishikawa 920-8640, Japan.
Hiroshi
H
Kawasaki
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D015415:Biomarkers; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000378:metabolism; D005289:Ferrets; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D054220:Malformations of Cortical Development / Q000209:etiology* / Q000473:pathology; D051379:Mice; D058953:Neural Stem Cells / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D010641:Phenotype; D012097:Repressor Proteins / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism; D013796:Thanatophoric Dysplasia / Q000209:etiology / Q000473:pathology
D015415:Biomarkers; C491198:Eomes protein, mouse; D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D051524:Fibroblast Growth Factor 8