Sox2 conditional mutation in mouse causes ataxic symptoms, cerebellar vermis hypoplasia, and postnatal defects of Bergmann glia

Abstract

Sox2 is a transcription factor active in the nervous system, within different cell types, ranging from radial glia neural stem cells to a few specific types of differentiated glia and neurons. Mutations in the human SOX2 transcription factor gene cause various central nervous system (CNS) abnormalities, involving hippocampus and eye defects, as well as ataxia. Conditional Sox2 mutation in mouse, with different Cre transgenes, previously recapitulated different essential features of the disease, such as hippocampus and eye defects. In the cerebellum, Sox2 is active from early embryogenesis in the neural progenitors of the cerebellar primordium; Sox2 expression is maintained, postnatally, within Bergmann glia (BG), a differentiated cell type essential for Purkinje neurons functionality and correct motor control. By performing Sox2 Cre-mediated ablation in the developing and postnatal mouse cerebellum, we reproduced ataxia features. Embryonic Sox2 deletion (with Wnt1Cre) leads to reduction of the cerebellar vermis, known to be commonly related to ataxia, preceded by deregulation of Otx2 and Gbx2, critical regulators of vermis development. Postnatally, BG is progressively disorganized, mislocalized, and reduced in mutants. Sox2 postnatal deletion, specifically induced in glia (with GLAST-CreERT2), reproduces the BG defect, and causes (milder) ataxic features. Our results define a role for Sox2 in cerebellar function and development, and identify a functional requirement for Sox2 within postnatal BG, of potential relevance for ataxia in mouse mutants, and in human patients.

Sox2 Acts in Thalamic Neurons to Control the Development of Retina-Thalamus-Cortex Connectivity

“…In fact, Sox2 functions are critical in stem cells of various types, in particular embryonic, neural, and others, in which it is necessary to preserve stemness (Avilion et al., 2003, Bertolini et al., 2016, Favaro et al., 2009, Kondoh and Lovell-Badge, 2016, Bertolini et al., 2019), and in the reprogramming of differentiated cells to stem cells (Takahashi and Yamanaka, 2016). In contrast, in several neural cell types such as differentiated neurons and glia, Sox2 is either not expressed, or important in very specific cell types, such as retinal Müller glia (Taranova et al., 2006) or cerebellar Bergmann glia (Cerrato et al., 2018).…”

Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology

“…These results provided the first in vivo evidence that astrocytes are critical for both cerebellar development and neuronal survival in the adult mouse brain. Along the same line, not only the lack of BG specification from cerebellar radial glia, due to the manipulation of several distinct genes, resulted in abnormal foliation and lamination and in locomotion defects [37][38][39][40] but also the incorrect maintenance of the BG phenotype (i.e., their ectopic location in the molecular layer and/or acquisition of a stellate morphology) during late postnatal development caused signs of ataxia in diverse mouse models [41,42]. Further, morphological defects of BG radial processes in vimentin-null mice also translated into impaired motor coordination, likely due to an aberrant structural and homeostatic support on PCs [43].…”

More than just Stem Cells: Functional Roles of the Transcription Factor Sox2 in Differentiated Glia and Neurons

“…BG cell bodies are found outside of the Purkinje cell layer, where they are usually localized, and their radial morphology is lost in Sox2 mutants (Figure 1A). Other glial cells that express Sox2, like parenchymal and prospective white matter astrocytes, appear unaffected by Sox2 loss, indicating a specific requirement for Sox2 in BG, but not in other glial cell types [29]. Since Wnt1-Cre-mediated Sox2 deletion occurs during early phases of embryogenesis, the observed phenotype could have been due to a problem occurring in the first phases of Bergmann glia differentiation from radial glia [40].…”

“…However, even postnatal conditional ablation of Sox2 in Bergmann glia—with a tamoxifen-inducible-Cre recombinase knocked-in the GLAST locus—showed that Sox2 is required to maintain BG radial morphology and their correct position in the PC-layer, in agreement with Sox2 maintaining an important role in postnatal, fully differentiated BG (Figure 1A). Interestingly, this later Sox2 ablation was accompanied by mild ataxia, while the vermis appeared normal, suggesting a likely direct role of Sox2-expressing BG in regulating neuronal activity [29]. One important role of BG that influences neuronal function, is the removal of glutamate from the synaptic cleft via the glutamate transporter GLAST.…”

“…Defects in glutamate uptake in humans lead to ataxia [43]. This function of BG seems to be influenced by Sox2 loss since Sox2 mutant BG were found defective in glutamate uptake [29].…”