miR-219 Cooperates with miR-338 in Myelination and Promotes Myelin Repair in the CNS.

A lack of sufficient oligodendrocyte myelination contributes to remyelination failure in demyelinating disorders. miRNAs have been implicated in oligodendrogenesis; however, their functions in myelin regeneration remained elusive. Through developmentally regulated targeted mutagenesis, we demonstrate that miR-219 alleles are critical for CNS myelination and remyelination after injury. Further deletion of miR-338 exacerbates the miR-219 mutant hypomyelination phenotype. Conversely, miR-219 overexpression promotes precocious oligodendrocyte maturation and regeneration processes in transgenic mice. Integrated transcriptome profiling and biotin-affinity miRNA pull-down approaches reveal stage-specific miR-219 targets in oligodendrocytes and further uncover a novel network for miR-219 targeting of differentiation inhibitors including Lingo1 and Etv5. Inhibition of Lingo1 and Etv5 partially rescues differentiation defects of miR-219-deficient oligodendrocyte precursors. Furthermore, miR-219 mimics enhance myelin restoration following lysolecithin-induced demyelination as well as experimental autoimmune encephalomyelitis, principal animal models of multiple sclerosis. Together, our findings identify context-specific miRNA-regulated checkpoints that control myelinogenesis and a therapeutic role for miR-219 in CNS myelin repair.

SVCT2 Overexpression in Neuroblastoma Cells Induces Cellular Branching that is Associated with ERK Signaling.

Expression of the sodium and ascorbic acid (AA) cotransporter SVCT2 is induced during the period of cellular arborization and synaptic maturation of early postnatal (P1-P5) rat cerebral neurons. The physiological importance of the transporter for neurons is evidenced by the lethality and delayed neuronal differentiation detected in mice with ablation of SVCT2. The mechanism(s) involved in these defects and the role of SVCT2 in neuronal branching have not been determined yet. To address this, we used lentiviral expression vectors to increase the levels of SVCT2 in N2a cells and analyzed the effects on neurite formation. Expression of a fusion protein containing the human SVCT2wt and EYFP induced an increase in the number of MAP2+ neurites and filopodia in N2a cells. Overexpression of SVCT2 and treatment with AA promoted ERK1/2 phosphorylation. Our data suggest that enhanced expression of the high affinity AA transporter SVCT2, which tightly regulates intracellular AA concentrations, induces neuronal branching that then activates key signaling pathways that are involved in the differentiation and maturation of cortical neurons during postnatal development.

Unconventional Neurogenic Niches and Neurogenesis Modulation by Vitamins.

Although the generation of new neurons occurs in adult mammals, it has been classically described in two defined regions of the brain denominated neurogenic niches: the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus. In these regions, neural stem cells give rise to new neurons and glia, which functionally integrate into the existing circuits under physiological conditions. However, accumulating evidence indicates the presence of neurogenic potential in other brain regions, from which multipotent precursors can be isolated and differentiated in vitro. In some of these regions, neuron generation occurs at low levels; however, the addition of growth factors, hormones or other signaling molecules increases the proliferation and differentiation of precursor cells. In addition, vitamins, which are micronutrients necessary for normal brain development, and whose deficiency produces neurological impairments, have a regulatory effect on neural stem cells in vitro and in vivo. In the present review, we will describe the progress that has been achieved in determining the neurogenic potential in other regions, known as unconventional niches, as well as the characteristics of the neural stem cells described for each region. Finally, we will revisit the roles of commonly known vitamins as modulators of precursor cell proliferation and differentiation, and their role in the complex and tight molecular signaling that impacts these neurogenic niches.