Progression of Fetal Brain Lesions in Tuberous Sclerosis Complex.

Antoinette Bernabe Gelot,Alfonso Represa

doi:10.3389/fnins.2020.00899

Abstract

Tuberous sclerosis (TSC) is a multisystem autosomal dominant genetic disorder due to loss of function of TSC1/TSC2 resulting in increased mTOR (mammalian target of rapamycin) signaling. In the brain, TSC is characterized by the formation of specific lesions that include subependymal and white matter nodules and cortical tubers. Cells that constitute TSC lesions are mainly Giant cells and dysmorphic neurons and astrocytes, but normal cells also populate the tubers. Although considered as a developmental disorder, the histopathological features of brain lesions have been described in only a limited number of fetal cases, providing little information on how these lesions develop. In this report we characterized the development of TSC lesions in 14 fetal brains ranging from 19 gestational weeks (GW) to term and 2 postnatal cases. The study focused on the telencephalon at the level of the caudothalamic notch. Our data indicate that subcortical lesions, forming within and at the vicinity of germinative zones, are the first alterations (already detected in 19GW brains), characterized by the presence of numerous dysmorphic astrocytes and Giant, balloon-like, cells. Our data show that cortical tuber formation is a long process that initiates with the presence of dysmorphic astrocytes (by 19–21GW), progress with the apparition of Giant cells (by 24GW) and mature with the appearance of dysmorphic neurons by the end of gestation (by 36GW). Furthermore, the typical tuberal aspect of cortical lesions is only reached when bundles of neurofilament positive extensions delineate the bottom of the cortical lesion (by 36GW). In addition, our study reveals the presence of Giant cells and dysmorphic neurons immunopositive for interneuron markers such as calbindin and parvalbumin, suggesting that TSC lesions would be mosaic lesions generated from different classes of progenitors.

Highlights

Tuberous sclerosis (TSC) is a systemic, autosomal dominant genetic disorder caused by mutations of TSC1 or TSC2 genes (Dragoumi et al, 2018; Hasbani and Crino, 2018) that result in a constitutive activation of mTORC1 disturbing subsequently cellular differentiation, proliferation, and migration early in development
The present study investigated the brains of 14 fetal cases covering the gestation period 19–39 weeks (GW), one term newborn deceased the 3th postnatal day and one infant case deceased the 8th postnatal month (Table 1)
The present data indicate that the cellular composition, the cytoarchitectonic organization and the distribution of TSC cells and lesions clearly evolve during fetal development confirming the progressive character of TSC lesions during pregnancy

Summary

Introduction

Tuberous sclerosis (TSC) is a systemic, autosomal dominant genetic disorder caused by mutations of TSC1 or TSC2 genes (Dragoumi et al, 2018; Hasbani and Crino, 2018) that result in a constitutive activation of mTORC1 disturbing subsequently cellular differentiation, proliferation, and migration early in development. Giant cells express markers of neural progenitors (SOX2, NESTIN, VIMENTIN and CD133) (Garbelli et al, 1999; Urbach et al, 2002; Ying et al, 2005; Lamparello et al, 2007; Yasin et al, 2010; Prabowo et al, 2013) and express in some cases markers of mature astrocytes (GFAP, S100β) or neurons (neurofilament, NeuN, Tuj, synaptophysin) (Garbelli et al, 1999; Urbach et al, 2002; Ying et al, 2005; Prabowo et al, 2013) From these observations it has been proposed that Balloon cells/Giant cells might derive from radial glial/stem cells (Lamparello et al, 2007; Yasin et al, 2010). The later may result from immune-inflammatory responses (for review see Aronica and Crino, 2014), though it was suggested that astrogliosis would result from the initial mutation of TSC1/TSC2 genes as many reactive astrocytes in the tubers express increased immunoreactivity for activated mTOR pathway components such are phospho-p70S6 kinase, phospho-S6 and phospho-STAT3 (Sosunov et al, 2008)

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Conclusion