Adult neural stem cells are astrocytes capable of neurogenesis in restricted regions of the brain. The largest neurogenic region is the subventricular zone (SVZ), which lines the lateral ventricles. Stem cell astrocytes give rise to new neurons in both homeostatic and regenerative conditions, suggesting that they are a pool of cells that can potentially be harnessed for regenerating the brain after injury, stroke, or neurodegenerative disease. A key step in recruiting adult neural stem cells for brain repair is to define the molecular pathways regulating their switch from a quiescent to an activated state. MicroRNAs are small non-coding RNAs that simultaneously target hundreds of mRNAs for degradation and translational repression. As such, they are excellent candidates to mediate stem cell activation. MicroRNAs have been implicated in stem cell self-renewal and differentiation and often exhibit altered expression in cancer. However their role in stem cell activation is unknown. Here, we show that the miR-17~92 cluster is highly enriched in activated adult neural stem cells as compared to their quiescent counterparts. The 17~92 cluster was first identified as an oncomiR, and stimulates proliferation and cell survival in tumors and in developing brain. I hypothesize that miR-17~92 cluster expression is key for activation of adult neural stem cells from the quiescent state by repressing negative regulators of EGFR signaling, which are upregulated in quiescent stem cells. We will conditionally manipulate levels of 17~92 expression to test our hypothesis that the cluster is necessary for activation and proliferation of adult neural stem cells. Finally, we will investigate whether negative regulators of EGFR signaling are key targets of the 17~92 cluster that mediate a quiescent state. Together, these findings will provide evidence for the first miRNA-based mechanism of adult neural stem cell activation via regulation of stem cell quiescence.
Endogenous adult stem cells exist in dormant and actively dividing states in the brain;however, the biological mechanisms driving the transition from one state to the other are unknown. This work will elucidate one possible mechanism of activating dormant stem cells. This will potentially help to develop therapies for brain repair and treatments for neurodegenerative diseases, stroke, and traumatic brain injuries.
| Codega, Paolo; Silva-Vargas, Violeta; Paul, Alex et al. (2014) Prospective identification and purification of quiescent adult neural stem cells from their in vivo niche. Neuron 82:545-59 |
