The RNA-Binding Protein RBM3 Promotes Neural Stem Cell (NSC) Proliferation Under Hypoxia

Abstract

Neural stem cells (NSCs) reside physiologically in a hypoxic niche to maintain self-renewal and multipotency. Whereas mild hypoxia is known to promote NSC proliferation, severe hypoxia in pathological conditions exerts the reverse effect. The multi-functional RNA-binding protein RBM3 is abundant in NSCs and can be regulated by hypoxic exposure. Although RBM3 has been shown to accelerate cell growth in many cell types, whether and how it affects NSC proliferation in hypoxic environment remains largely unknown. In this study, we tested how RBM3 regulates cell proliferation under hypoxia in C17.2 mouse NSC cell line and in primary mouse NSCs from both the forebrain of postnatal day 0 (P0) mice and the subgranular zone (SGZ) of adult mice. Our results demonstrated that RBM3 expression was highly sensitive to hypoxia, and NSCs were arrested in G0/G1 phase by 5, 2.5, and 1% O2 treatment. When we overexpressed RBM3, hypoxia-induced cell cycle arrest in G0/G1 phase was relieved and more cell transit into S phase was observed. Furthermore, cell viability under hypoxia was also increased by RBM3. In contrast, in RBM3-depleted primary NSCs, less BrdU-incorporated cells were detected, indicating exacerbated cell cycle arrest in G1 to S phase transition. Instead, overexpressed RBM3 significantly increased proliferation ratio in primary NSCs. Our findings indicate RBM3 as a potential target to maintain the proliferation capacity of NSCs under hypoxia, which can be important in NSC-based therapies of acute brain injury and chronic neurodegenerative diseases.

Proteomic-Based Analysis of Hypoxia- and Physioxia-Responsive Proteins and Pathways in Diffuse Large B-Cell Lymphoma

“…Intriguingly, downregulation of the cell cycle was also noticed in U2904 cells under physioxia; however, in hypoxic Ri-1 cells, the upregulation of M Phase and G2/M transition pathway was observed. The influence of physiological oxygen on the cell cycle is still not well understood; however, studies show mostly acceleration in cell proliferation under physioxia [10,51,78,79]. Notably, in our previously published data, we established that the Ri-1 cell line growth was significantly decreased in physioxia and hypoxia after 96 h of treatment, while the proliferative capability of the remaining cell lines was unchanged [78].…”

The mRNA-Binding Protein RBM3 Regulates Activity Patterns and Local Synaptic Translation in Cultured Hippocampal Neurons

“…Several studies have demonstrated that RBM3 enhances polysome formation, by phosphorylation of translation initiation factors and by changing the miRNA level ( Chappell et al, 2001 ; Dresios et al, 2005 ). RBM3 has been described to enhance the translation of specific genes in hypothermia, thereby protecting synaptogenesis ( Yan et al, 2019 ; Zhu et al, 2019 ). Moreover, although RBM3 is primarily located at the nucleus, one isoform has been found in dendrites, where it colocalizes with a ribosomal protein ( Smart et al, 2007 ).…”

“…Several studies have demonstrated that RBM3 enhances polysome formation, by phosphorylation of translation initiation factors and by changing the microRNA level (Chappell et al, 2001;Dresios et al, 2005). RBM3 has been described to enhance the translation of specific genes in hypothermia, thereby protecting synaptogenesis (Yan et al, 2019;Zhu et al, 2019).…”

The role of hypoxia in stem cell regulation of the central nervous system: From embryonic development to adult proliferation

“… 33 RNA‐binding protein RBM3 was found to be highly upregulated in response to hypoxia, which in turn increased proliferation of primary NSCs. 34 In addition, gene set enrichment analysis identified the calcium‐regulated transcription factor NFATc4, which is significantly upregulated in NSCs after hypoxia treatment, as a potential candidate in the regulation of hypoxic NSC functions. 35 Therefore, hypoxia plays an important role in the development and differentiation of NSCs and NPCs and suggests that understanding the molecular mechanism of hypoxia‐mediated behavioral changes in NSCs and NPCs is helpful to optimize stem cell therapies for neurological diseases.…”