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.
Highlights
Was found to be a prominent phenotype of mouse TD, like human TD
We have shown that fibroblast growth factor 8 (FGF8)-transfected ferrets have polymicrogyria, megalencephaly and subependymal heterotopia, which are common features of human TD patients
Our histological analyses indicate that outer radial glial cells (oRGs) and intermediate progenitor cells (IPs) are increased in the subventricular zone (SVZ) of TD ferrets
Summary
The cortex in mouse TD did not form abnormal sulci and gyri, human TD patients have abnormalities in the cortical gyri[18,19]. To manipulate gene expression in the ferret cerebral cortex, we recently established a rapid and efficient gene manipulation technique for ferrets using in utero electroporation[24,25]. Using this technique, here we successfully produced the cortical phenotypes of TD by expressing fibroblast growth factor 8 (FGF8) in the ferret cerebral cortex. Our findings should help shed light on the molecular mechanisms underlying the formation and malformation of the cortical gyrus in higher mammals
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