MicroRNA - a contributor to age-associated neural stem cell dysfunction?

the adult mammalian brain, new neurons are continuously generated from neural stem cells in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampus [1].Increasing evidence for the functional importance of adult-generated neurons in these regions for learning, complex behavior, and mood regulation, as well as a potential link of impaired adult neurogenesis to cognitive deficits in ageing and neurodegeneration have sparked great interest in the regulatory mechanisms underlying the coordinated generation of new functional neurons. Neurogenesis includes self-renewal and fate specification of neural stem cells, migration and maturation of young neurons, and functional integration of new neurons into the neural circuitry [1]. A large body of work has demonstrated that neurogenesis is regulated in a complex manner by the dynamic interplay of cell-extrinsic signals derived from the neurogenic " niche " and cell-intrinsic transcriptional and epigenetic regulators. More recently, microRNAs (miRNAs) have emerged as potent modulators of adult neurogenesis. miRNA 132 has been linked to the maturation and functional integration of newly generated hippocampal neurons and – in this context – is potentially regulated by hippocampal network activity and CREB-signalling [2]. Several miRNAs have also been implied in controlling the balance of stem cell maintenance and differentiation-a crucial checkpoint for sustaining adult neurogenesis throughout adulthood. In this context, miRNA-137 [3] and miRNA-184 [4] have been found to promote stem cell maintenance at the expense of differentiation, while miRNA-9 [5], miRNA lethal-7b (let-7b) [6, 7], and miRNA-124 [8] tip the balance from stem cell maintenance towards differentiation through Commentary the negative regulation of cyclin D1 and the stem cell maintenance factors TLX, Hmga2, and Sox9. Intriguingly, the latter factors are transcriptional regulators and thus are likely to control the expression of larger sets of genes, which may explain the profound effects of those miRNAs in stem cell maintenance and differentiation. In the February issue of Aging Brett and colleagues link the microRNA cluster miR-106b~25 to neural stem cell expansion and neuronal differentiation [9]. In this work, they demonstrate that miR-106b~25 promotes proliferation in primary neural stem cell cultures. Moreover they report that overexpression of miR-106b~25 enhances neural stem cell differentiation toward the neuronal lineage. Although the in vitro modulatory effects of miRNA-106b~25 on neural stem cell behaviour are relatively modest, the authors made several notable observations that imply this miRNA cluster as a critical regulator of adult neurogenesis and warrant further investigation of its …