The Role of miRNA in Neurogenesis and Cell Specification

Abstract: Only a few decades ago, it was generally believed that gene expression was controlled in a unidirectional way, i.e. DNA was transcribed into RNA, which simply acted as a messenger molecule used to produce the protein that executed cellular functions. It was not until the 1970-80’s that RNA interference was proclaimed as a gene regulatory process, and now it is increasingly evident that non-coding RNA has a large impact on regulating and fine-tuning gene expression. microRNA (miRNA) constitute one of the largest classes of non-coding RNA. They are endogenously expressed, 19-23 nucleotides long and act by inhibiting or degrading mRNA. miRNA control vital cellular and biologic processes, and importantly for the work in this thesis, they are implicated in regulating neuronal development and neurogenesis. Neurogenesis, the generation of new neurons, is primarily restricted to two niches of the adult brain. The molecular knowledge of how adult neurogenesis is regulated, and how different cell types are specified, is of great importance to understand how the brain functions in health and disease. In my thesis, I have been studying the involvement of miRNA in adult neurogenesis and in cell type specification. Using transgenic miRNA sensor mice, I have investigated the activity of three different miRNA expressed in the brain; miR-124, miR-9 and miR-125. The analyses of the sensor mice have revealed new information about the expression of these miRNA in the brain, presented in papers I-III. In the first study, we demonstrated that miR-124 is a neuronal fate determinant in the postnatal subventricular zone, balancing neurogenesis and gliogenesis. In the second study, we found that miR-9 is specifically absent from resident microglia in the brain, and that miR-9-regulated vectors can be used to visualise and isolate this cell type. In the third study, we showed that miR-125 is expressed in most cells of the brain, except for the interneurons in the olfactory bulb that are generated during development, suggesting that absence of an otherwise broadly expressed miRNA is a mechanism to achieve neuronal subtype specification. Thus, I have used novel tools and techniques to study the activity of miRNA in the brain and to modulate the expression of individual miRNA in different cell types. I provide new insights into the important roles of miRNA in neurogenesis and in cell specification.