Assessment of radial glia in the frontal lobe of fetuses with Down syndrome

Ana A Baburamani,J Donald Tournier,Alena Uus,Mary A Rutherford,Maximilian Pietsch,Veena G Supramaniam,Maria Deprez,Prachi A Patkee,Regina T Vontell,Evonne C Chin-Smith,Jo Wyatt-Ashmead

doi:10.1186/s40478-020-01015-3

Ana A Baburamani, J Donald Tournier + Show 9 more

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https://doi.org/10.1186/s40478-020-01015-3

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Abstract

Down syndrome (DS) occurs with triplication of human chromosome 21 and is associated with deviations in cortical development evidenced by simplified gyral appearance and reduced cortical surface area. Radial glia are neuronal and glial progenitors that also create a scaffolding structure essential for migrating neurons to reach cortical targets and therefore play a critical role in cortical development. The aim of this study was to characterise radial glial expression pattern and morphology in the frontal lobe of the developing human fetal brain with DS and age-matched controls. Secondly, we investigated whether microstructural information from in vivo magnetic resonance imaging (MRI) could reflect histological findings from human brain tissue samples. Immunohistochemistry was performed on paraffin-embedded human post-mortem brain tissue from nine fetuses and neonates with DS (15–39 gestational weeks (GW)) and nine euploid age-matched brains (18–39 GW). Radial glia markers CRYAB, HOPX, SOX2, GFAP and Vimentin were assessed in the Ventricular Zone, Subventricular Zone and Intermediate Zone. In vivo diffusion MRI was used to assess microstructure in these regions in one DS (21 GW) and one control (22 GW) fetal brain. We found a significant reduction in radial glial progenitor SOX2 and subtle deviations in radial glia expression (GFAP and Vimentin) prior to 24 GW in DS. In vivo, fetal MRI demonstrates underlying radial projections consistent with immunohistopathology. Radial glial alterations may contribute to the subsequent simplified gyral patterns and decreased cortical volumes observed in the DS brain. Recent advances in fetal MRI acquisition and analysis could provide non-invasive imaging-based biomarkers of early developmental deviations.

Highlights

Down syndrome (DS) is the most frequent genetic cause of intellectual disability, with approximately 750 babies born annually in the UK
In our mid-gestation (15+6–24+2 gestational weeks (GW)) cohort; we qualitatively described the pattern of radial glia staining (CRYAB, HOPX, SOX2, glial fibrillary acidic-protein (GFAP), Vimentin) in the ventricular zone (VZ)/ inner SVZ (iSVZ)
Based on haematoxylin and eosin (H&E) staining, DS cases from 20 GW (3/3 cases; Fig. 1e) showed that the cortical plate (CP) and the VZ had a sparse cellular pattern when compared to the euploid controls (Fig. 1d)

Summary

Introduction

Down syndrome (DS) is the most frequent genetic cause of intellectual disability, with approximately 750 babies born annually in the UK. The over-expression of genes on HSA21, their associated pathways in addition to activation of global cellular responses and compensatory mechanisms of genes not on HSA21, are all thought to promote the atypical phenotypes observed in DS [16, 37, 38]. Human post-mortem studies of the fetal and neonatal brain with DS have described decreases in total and neuronal cell numbers, abnormal neuronal maturation, and altered lamination of the cortex which may contribute to the observed reductions in brain volumes [14, 32, 50, 54, 63], as seen on MRI. In fetuses with DS, decreased proliferation and increased cell death have been observed before 21 gestational weeks (GW) [7, 37, 38]

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