Role of small noncoding RNAs in mammalian adult neurogenesis

Neurogenesis is the process of new neuron (and glia) generation from Neural Stem Cells (NSCs). NSCs self-renew and generate committed offspring in a tightly regulated fashion. The balance between NSC proliferation and differ- entiation guarantees brain formation, lifelong neurogenesis and prevents tumor formation. Regulation of neurogenesis is crucial but remains unclear. Understanding this regulation has implications for comprehending brain (mal)formation, mainte- nance of the capability to generate new neurons throughout life preventing age-related disorders and brain cognition. Adult hippocampal neurogenesis attracts considerable attention from neu- roscientists and the general public because of its suggestive appeal and presumed relevance for cognition in health and disease. It comprises a complex cascade of events, starting with the activation of quiescent resident NSC, followed by asym- metric cell division, rendering a new stem cell and a daughter neural progenitor. Neural progenitors then amplify through symmetric divisions and undergo cell fate decisions, whereas some cells are depleted through apoptosis. The surviving neural progenitors can then differentiate into immature neurons or astrocytes, which over time, will mature and integrate into the pre-existing neuronal net- work. Each of these steps in this cascade requires complex and rapid changes in the molecular machinery, which usually comprise multiple levels of molecular control. The field of neurogenesis has been for long dominated by genetics, but protein- coding genes account for only 2% of the human genome. In contrast, 98% of the human genome encodes noncoding RNAs with gene-regulatory functions and nearly half of genome is comprised of Transposable Elements (TEs), which are highly active during neurogenesis. Moreover, noncoding RNAs are par- ticularly relevant for the regulation of neurogenesis both in developing and in the adult brain. It follows that a better understanding of noncoding RNAs is essential to complete the puzzling mechanism of neurogenesis. The aim of my PhD project is to better understand and characterize the role of two classes of small noncoding RNAs, namely microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs) in the regulation of adult neurogenesis. The work reported in my thesis provides fundamental insight on the role of small noncoding RNAs in adult neurogenesis: First, the discovery of a crucial role of the Piwi-pathway in the maintenance of postnatal neurogenesis, opens the possibility to targets this pathway for therapy in the context of ageing and age-related brain dysfunctions, such as neurodegeneration. Second, the finding that inhibition of miR-135, a miRNA that is key mediator of physical activity, in 2 years old (equivalent to 70 years old human) sedentary mice is sufficient to rescue neurogenesis to young levels offers intriguing perspectives towards therapeutic uses of miRN-135 inhibitors to delay or prevent brain aging and related brain pathologies.