Relative Levels of Gli1 and Gli2 Determine the Response of Ventral Neural Stem Cells to Demyelination

Abstract

Enhancing repair of myelin is an important therapeutic goal in many neurological disorders characterized by demyelination. In the healthy adult brain, ventral neural stem cells (vNSCs) in the subventricular zone, marked by GLI1 expression, do not generate oligodendrocytes. However, in response to demyelination, their progeny are recruited to lesions where they differentiate into oligodendrocytes and ablation of GLI1 further enhances remyelination. GLI1 and GLI2 are closely related transcriptional activators but the role of GLI2 in remyelination by vNSCs is not clear. Here, we show that genetic ablation of Gli1 in vNSCs increases GLI2 expression and combined loss of both transcription factors decreases the recruitment and differentiation of their progeny in demyelinated lesions. These results indicate that GLI1 and GLI2 have distinct, non-redundant functions in vNSCs and their relative levels play an essential role in the response to demyelination.

Smoothened/AMP-Activated Protein Kinase Signaling in Oligodendroglial Cell Maturation

“…In addition, our experiments using DRS lead us to propose that GSA-10-mediated Gli2 upregulation requires AMPK activation. Since Gli1 ablation has been proposed previously to increase Gli2 expression in vivo, as especially shown in NSCs upon CNS demyelination (Radecki et al, 2020), we may hypothesize that the partial impairment of GSA-10mediated Gli1 downregulation induced by DRS in Oli-neuM cells may subsequently prevent Gli2 upregulation. This hypothesis would further corroborate the importance of relative expression levels of the two transcription factors in the context of myelin production (Radecki et al, 2020).…”

“…We reasoned that the ability of GSA-10 to activate a non-canonical Smo signaling pathway resulting in Gli1 downregulation and Gli2 upregulation might promote the recruitment of NPCs, as recently shown for the Gli1 antagonist GANT-61 (Samanta et al, 2015;Namchaiw et al, 2019;Radecki et al, 2020). To validate this idea, a stereotactic injection of LPC was performed into the corpus callosum in the presence of GSA-10 in order to determine the effects of non-canonical Smo modulation on the recruitment of oligodendroglial cells upon CNS demyelination.…”

Histological Studies of the Ventricular–Subventricular Zone as Neural Stem Cell and Glioma Stem Cell Niche

“…11,[16][17][18][19][20] Specific subregions of the V-SVZ also generate oligodendrocytes, which contribute to white matter structures such as the corpus callosum. [21][22][23][24][25] Although studies in the rodent have been highly informative in studying core pathways regulating the organization, persistence, and activation of stem cells within the V-SVZ niche, 26 some key differences exist between mouse and human, which are relevant to studies of the normal and cancerous brain. As explored in the discussion of other stem cell niches below, the extent of olfactory bulb neurogenesis in human brain has been subject to conflicting reports.…”

Transcriptomic analysis of loss of Gli1 in neural stem cells responding to demyelination in the mouse brain

“…The brain was removed gently out of the skull and immediately transferred to a Petri dish chilled on ice and placed with the dorsal surface facing up on a chilled acrylic mouse brain matrix. The brains of mice were dissected according to previously published protocols 40 . Coronal sections of 1mm thickness were made from the rostral end of the brain up to the dorsal hippocampus posteriorly, using a sharp and chilled razor blade.…”