Pathophysiological analyses of periventricular nodular heterotopia using gyrencephalic mammals

Abstract

Although periventricular nodular heterotopia (PNH) is often found in the cerebral cortex of people with thanatophoric dysplasia (TD), the pathophysiology of PNH in TD is largely unknown. This is mainly because of difficulties in obtaining brain samples of TD patients and a lack of appropriate animal models for analyzing the pathophysiology of PNH in TD. Here we investigate the pathophysiological mechanisms of PNH in the cerebral cortex of TD by utilizing a ferret TD model which we recently developed. To make TD ferrets, we electroporated fibroblast growth factor 8 (FGF8) into the cerebral cortex of ferrets. Our immunohistochemical analyses showed that PNH nodules in the cerebral cortex of TD ferrets were mostly composed of cortical neurons, including upper layer neurons and GABAergic neurons. We also found disorganizations of radial glial fibers and of the ventricular lining in the TD ferret cortex, indicating that PNH may result from defects in radial migration of cortical neurons along radial glial fibers during development. Our findings provide novel mechanistic insights into the pathogenesis of PNH in TD.

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

“…34) The number of oRG cells was significantly reduced by the dominant-negative FGFR, 34) whereas it was markedly increased by FGF8. 31) These results indicate that FGF signaling plays a pivotal role in producing oRG cells in the OSVZ. Furthermore, our finding raised the possibility that oRG cells mediate cortical folding downstream of FGF signaling.…”

“…Interestingly, our results demonstrated that genetic manipulation of Cdk5 and FGF signaling, which have been reported responsible for human patients with malformation of cortical folds, 23,42,59,60) also produced similar phenotypes in ferrets. 10,31,34) This suggests that similar mechanisms are used to make cortical folds in ferrets and humans. Because marmosets and ferrets have their own unique features, combining transgenic marmosets and electroporated ferrets would facilitate our understanding of the brain of higher mammals.…”

“…To test this point, we expressed fibroblast growth factor 8 (FGF8), which has a high affinity to FGFR3, into the ferret cerebral cortex using our technique. 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.…”

“…As described above, introduction of FGF8 into the ferret cortex resulted in polymicrogyria, suggesting that activation of FGF signaling is sufficient for producing cortical folds. 31) Therefore, we next examined the role of endogenous FGF signaling in cortical folding. 34) We first examined the expression of FGFRs and found that FGFR1, FGFR2, and FGFR3 are expressed in the developing ferret cortex.…”

Gyrification of the cerebral cortex requires FGF signaling in the mammalian brain

“…In situ hybridization was performed as described previously ( Matsumoto et al, 2017 ). Sections prepared from fresh-frozen or fixed tissues were treated with 4% PFA for 10 min, 1 µg/ml proteinase K for 10 min and 0.25% acetic anhydride for 10 min.…”