The multiple roles of cold-inducible RBM3 in neural stem cells after hypoxia-ischemia injury

Abstract

Hypoxia-ischemia (HI) inflicts devastating brain injury across all age groups. In clinical practice, therapeutic hypothermia (32–34 °C) has proved a potent tool for alleviating neurological deficit in infants with hypoxia-ischemia encephalopathy and in adults with acute brain injury. Previous reports from our group and others have shown RNA-binding motif protein 3 (RBM3) to be neuroprotective under various stressful conditions through diverse cellular and molecular mechanisms. In the first part of this thesis, we used RBM3 mutant mice to find out how RBM3 promotes ischemia-induced neurogenesis and how it regulates cell proliferation during hypoxia. We showed how RBM3 stimulates neuronal differentiation and inhibits HI-induced apoptosis in the two areas of persistent adult neurogenesis, the subventricular zone (SVZ) and subgranular zone (SGZ), while promoting neural stem/progenitor cell (NSC) proliferation after HI injury only in the SGZ. RBM3 interacts with IGF2 mRNA binding protein 2 (IMP2), elevates its expression and thereby stimulates IGF2 release in SGZ- but not SVZ-NSCs. In summary, we describe niche-dependent regulation of neurogenesis after adult HI injury via the novel RBM3–IMP2–IGF2 signaling pathway. In the second part we analyze the effect of hypoxia on the expression of multifunctional RBM3 and how this protein in turn regulates cell proliferation and death. Our findings identify RBM3 as a potential target for maintaining NSC proliferation capacity during hypoxia, which can be important in NSC-based therapies of acute brain injury and chronic neurodegenerative disease. We devote the third part to ascertaining the functions of RBM3 and IMP2 in neuroblastoma proliferation and differentiation.