Abstract
Cellular metabolism plays a crucial role in controlling the proliferation, differentiation, and quiescence of neural stem cells (NSCs). The metabolic transition from aerobic glycolysis to oxidative phosphorylation has been regarded as a hallmark of neuronal differentiation. Understanding what triggers metabolism reprogramming and how glucose metabolism directs NSC differentiation may provide new insight into the regenerative potential of the brain. TP53 inducible glycolysis and apoptosis regulator (TIGAR) is an endogenous inhibitor of glycolysis and is highly expressed in mature neurons. However, its function in embryonic NSCs has not yet been explored. In this study, we aimed to investigate the precise roles of TIGAR in NSCs and the possible involvement of metabolic reprogramming in the TIGAR regulatory network. We observed that TIGAR is significantly increased during brain development as neural differentiation proceeds, especially at the peak of NSC differentiation (E14.5–E16.5). In cultured NSCs, knockdown of TIGAR reduced the expression of microtubule-associated protein 2 (MAP2), neuron-specific class III beta-tubulin (Tuj1), glial fibrillary acidic protein (GFAP), Ngn1, and NeuroD1, and enhanced the expression of REST, suggesting that TIGAR is an important regulator of NSC differentiation. Furthermore, TIGAR enhanced the expression of lactate dehydrogenase B (LDHB) and the mitochondrial biogenesis and oxidative phosphorylation (OXPHOS) markers, peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1α), nuclear respiratory factor (NRF1), and MitoNEET during NSC differentiation. TIGAR can decrease lactate production and accelerate oxygen consumption and ATP generation to maintain a high rate of OXPHOS in differentiated NSCs. Interestingly, knockdown of TIGAR decreased the level of acetyl-CoA and H3K9 acetylation at the promoters of Ngn1, Neurod1, and Gfap. Acetate, a precursor of acetyl-CoA, increased the level of H3K9 acetylation and rescued the effect of TIGAR deficiency on NSC differentiation. Together, our data demonstrated that TIGAR promotes metabolic reprogramming and regulates NSC differentiation through an epigenetic mechanism.
Highlights
neural stem cells (NSCs) are defined by their capacity for self-renewal and for differentiation into neurons, astrocytes, and oligodendrocytes[1]
Similar results were obtained in immunostaining experiments, and TP53 inducible glycolysis and apoptosis regulator (TIGAR) was widely distributed in the embryonic cortex, as indicated by its localization in the ventricular zone (VZ), the subventricular zone (SVZ) and the cortical plate (CP) at E16.5 (Fig. 1c, d)
By immunofluorescent staining for TIGAR and Nestin or Sox[2], we found that TIGAR is localized in the cytoplasm of NSCs (Fig. 1e, f)
Summary
NSCs are defined by their capacity for self-renewal and for differentiation into neurons, astrocytes, and oligodendrocytes[1]. NSCs can generate new neurons in the Official journal of the Cell Death Differentiation Association. Given the important role of metabolism in regulating the proliferation and differentiation of NSCs, pharmacological intervention in metabolic homeostasis may be able to exploit the regenerative potential of NSCs against these neurodegenerative diseases. TIGAR is generally regarded as an antiapoptotic gene expressed in response to p53-induced cell death. TIGAR is highly expressed in human breast carcinoma cells. Recent evidence showed that overexpression of TIGAR in carcinoma cells altered metabolic compartmentalization to a mitochondrial metabolic phenotype and increased tumor growth[7]. TIGAR is widely distributed in neurons and plays crucial roles in the central nervous system (CNS). In the developing brain, the effect of TIGAR in NSCs is largely unknown
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