Abstract
The neocortex, the most recently evolved brain region in mammals, is characterized by its unique areal and laminar organization. Distinct cortical layers and areas can be identified by the presence of graded expression of transcription factors and molecular determinants defining neuronal identity. However, little is known about the expression of key master genes orchestrating human cortical development. In this study, we explored the expression dynamics of NR2F1 and SOX2, key cortical genes whose mutations in human patients cause severe neurodevelopmental syndromes. We focused on physiological conditions, spanning from mid-late gestational ages to adulthood in unaffected specimens, but also investigated gene expression in a pathological context, a developmental cortical malformation termed focal cortical dysplasia (FCD). We found that NR2F1 follows an antero-dorsallow to postero-ventralhigh gradient as in the murine cortex, suggesting high evolutionary conservation. While SOX2 is mainly expressed in neural progenitors next to the ventricular surface, NR2F1 is found in both mitotic progenitors and post-mitotic neurons at GW18. Interestingly, both proteins are highly co-expressed in basal radial glia progenitors of the outer sub-ventricular zone (OSVZ), a proliferative region known to contribute to cortical expansion and complexity in humans. Later on, SOX2 becomes largely restricted to astrocytes and oligodendrocytes although it is also detected in scattered mature interneurons. Differently, NR2F1 maintains its distinct neuronal expression during the whole process of cortical development. Notably, we report here high levels of NR2F1 in dysmorphic neurons and NR2F1 and SOX2 in balloon cells of surgical samples from patients with FCD, suggesting their potential use in the histopathological characterization of this dysplasia.
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This research was supported by the Italian Ministry of Health (C.F.) and European Research Area Networks (ERA-NET) Neuron II (Improv-Vision) grant supporting C.F. (RE7-No. 363/2016), S.N. and M.S. (ANR-15-NEUR-0002-04).
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429_2021_2242_MOESM1_ESM.tif
Supplementary file 1 Supplementary Figure 1: Comparison of NR2F1 and SOX2 expression in adult autoptic and post-surgical non-malformed cortex. A-F: Representative paraffin sections from autoptic control case (A, C, E- sample 11) and post-surgical non-malformed temporal cortex (B, D, F, sample 13) showing NR2F1 and SOX2 expression. Note the comparable NR2F1 expression in the two different cases, whereas SOX2+ cells seem to be underestimated in autoptic samples. Scale bars: 6 mm in A-B; 100 μm in C-F. (TIF 6631 KB)
429_2021_2242_MOESM2_ESM.tif
Supplementary file 2 Supplementary Figure 2: NR2F1 and SOX2 expression in abnormal cells in Focal Cortical Dysplasia. A-F: Examples of dysmorphic neurons (A, thionin) positive for NR2F1 (B, D, E) but negative for SOX2 (C, F). G-I: Examples of balloon cells positive for both NR2F1 (G) and SOX2 (H, I). (Samples 15,16,19). Scale bars: 50 μm in A-C; 35 μm in D-I. (TIF 12087 KB)
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Foglio, B., Rossini, L., Garbelli, R. et al. Dynamic expression of NR2F1 and SOX2 in developing and adult human cortex: comparison with cortical malformations. Brain Struct Funct 226, 1303–1322 (2021). https://doi.org/10.1007/s00429-021-02242-7
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DOI: https://doi.org/10.1007/s00429-021-02242-7