C-Terminal Binding Proteins Promote Neurogenesis and Oligodendrogenesis in the Subventricular Zone

Abstract

C-terminal binding proteins (CtBPs) are transcriptional modulators that can regulate gene expression through the recruitment of a corepressor complex composed of chromatin-modifying enzymes and transcriptional factors. In the brain, CtBPs have been described as regulators of cell proliferation, differentiation, and survival. Nevertheless, the role of CtBPs on postnatal neural stem cells (NSCs) fate is not known yet. Herein, we evaluate the expression and functions of CtBPs in postnatal NSCs from the subventricular zone (SVZ). We found that CtBPs were expressed in immature/progenitor cells, neurons and glial cells in the SVZ niche. Using the CtBPs modulator 4-methylthio 2-oxobutyric acid (MTOB), our results showed that 1 mM of MTOB induced cell death, while 5, 25, and 50 μM increased the number of proliferating neuroblasts, mature neurons, and oligodendrocytes. Interestingly, it also increased the dendritic complexity of immature neurons. Altogether, our results highlight CtBPs putative application for brain regenerative applications.

CtBP Neuroprotective Role in Toxin-Based Parkinson’s Disease Models: From Expression Pattern to Dopaminergic Survival

“…So far, MTOB was used in brain cells mainly at high concentrations (1-5 mM), leading to apoptosis [17,23]. In a previous report, we showed that low levels of MTOB (up 100 µM) were not toxic to neural stem cell cultures and promoted neuronal differentiation and maturation, and oligodendrogenesis [17], suggesting that CtBP may co-activate genes beneficial for brain regeneration. Herein, we observed a toxic effect of MTOB per se at high concentrations, namely at 1000 µM and 2500 µM.…”

“…Interestingly, a missense mutation on CtBP1 was found in patients presenting neurodevelopmental deficits (e.g., ataxia, intellectual disability), further supporting the role of CtBP in central nervous system development [16]. Recently, we have demonstrated that CtBP are expressed in subventricular zone neural stem/progenitor cells, and the exposure of neonatal neural stem cell cultures to an unspecific ligand of CtBP, the 4-methylthio 2-oxobutyric acid (MTOB), resulted in enhanced neurogenesis and neuronal complexity as well as increased oligodendrogenesis indicating their potential for regenerative therapies [17].…”

“…It acts as an inhibitor for CtBP at high concentrations (millimolar range), inhibiting the recruitment of CtBP to several target promoters, including pro-apoptotic promoters, and, therefore, decreasing the survival of several tumor cell lines and tumor growth in vivo [35,36]. So far, MTOB was used in brain cells mainly at high concentrations (1-5 mM), leading to apoptosis [17,23]. In a previous report, we showed that low levels of MTOB (up 100 µM) were not toxic to neural stem cell cultures and promoted neuronal differentiation and maturation, and oligodendrogenesis [17], suggesting that CtBP may co-activate genes beneficial for brain regeneration.…”