Pathophysiological analyses of leptomeningeal heterotopia using gyrencephalic mammals

Abstract

Leptomeningeal glioneuronal heterotopia (LGH) is a focal malformation of the cerebral cortex and frequently found in patients with thanatophoric dysplasia (TD). The pathophysiological mechanisms underlying LGH formation are still largely unclear because of difficulties in obtaining brain samples from human TD patients. Recently, we established a new animal model for analysing cortical malformations of human TD by utilizing our genetic manipulation technique for gyrencephalic carnivore ferrets. Here we investigated the pathophysiological mechanisms underlying the formation of LGH using our TD ferrets. We found that LGH was formed during corticogenesis in TD ferrets. Interestingly, we rarely found Ki-67-positive and phospho-histone H3-positive cells in LGH, suggesting that LGH formation does not involve cell proliferation. We uncovered that vimentin-positive radial glial fibers and doublecortin-positive migrating neurons were accumulated in LGH. This result may indicate that preferential cell migration into LGH underlies LGH formation. Our findings provide novel mechanistic insights into the pathogenesis of LGH in TD.

Molecular Investigations of the Development and Diseases of Cerebral Cortex Folding using Gyrencephalic Mammal Ferrets

“…31) We successfully recapitulated the cortical phenotypes of TD by expressing FGF8 in the ferret cerebral cortex. 31) Strikingly, our TD ferret model showed not only megalencephaly but also polymicrogyria, periventricular nodular heterotopia and leptomeningeal heterotopia [31][32][33] (Fig. 3).…”

Roots of the Malformations of Cortical Development in the Cell Biology of Neural Progenitor Cells

“…Pharmacological inhibition of mitosis is used to generate a ferret model of cortical dysplasia ( Noctor et al, 1999 , 2001 ). In utero electroporation of ferrets ( Kawasaki et al, 2012 , 2013 ; Kalebic et al, 2020 ), which has been used to deliver human-specific genes and thereby further enforce ferret’s potential to model human brain characteristics ( Kalebic et al, 2018 ), has been used to model lissencephaly ( Shinmyo et al, 2017 ) and thanatophoric dysplasia ( Masuda et al, 2015 ; Matsumoto et al, 2017a , b , 2018 ). Transgenic ferrets with a germline knockout of Aspm were generated as a model for microcephaly ( Johnson et al, 2018 ).…”

“…Mouse model of the thanatophoric dysplasia successfully recapitulated the megalencephaly phenotype, but not the other abnormalities ( Lin et al, 2003 ). Instead the ferret model recapitulated all the other phenotypes found in human patients, such as polymicrogyria ( Masuda et al, 2015 ), periventricular nodular heterotopia ( Matsumoto et al, 2017a ) and leptomeningeal glioneuronal heterotopia ( Matsumoto et al, 2018 ). Similarly to FGF signaling, insulin growth factor (IGF) signaling through IGF1R (type 1 IGF receptor) stimulates progenitor proliferation and mutations in IGF1R were detected in patients with brain overgrowth ( Faivre et al, 2002 ; Joseph D’Ercole and Ye, 2008 ).…”

Enhanced FGFR3 activity in postmitotic principal neurons during brain development results in cortical dysplasia and axonal tract abnormality

“…Ectopic neurons accumulating in the dentate gyrus were also observed 19 . Moreover, overexpressing FGF8 ligand to enhance FGFR signaling in a ferret resulted in megalencephaly, polymicrogyria, subependymal heterotopia, and leptomeningeal heterotopia 106 , 107 . In contrast to previous studies, the GOF mouse generated in this study by overexpressing FGFR3 K650E in NEX-lineage neurons exhibited a severe cortical lamination defect (Figs.…”