Conditional deletion of Dicer from a subset of hippocampal neurons results in cell-autonomous changes in dendritic morphology

MicroRNAs (miRNAs) are a class of small, non-coding RNA molecules involved in the post-transcriptional repression of target mRNAs. The gene silencing activity of miRNAs is important for a range of cellular processes including cell differentiation, proliferation, and cell cycle regulation. As part of a complex set of processing steps, a pre-miRNA hairpin structure is processed by an enzyme called Dicer into the mature miRNA. As, such, Dicer has been targeted using gene disruption approaches to gain insight into the functional role of miRNAs. Using these approaches, work to date in the central nervous system has shown that Dicer knockout mice exhibit disrupted neuronal maturation, and even neuronal death. Although these findings provide important information regarding the role of miRNA in the developing nervous system, we still know relatively little about the function of miRNA in the mature CNS. To begin to address this question, we employed a tamoxifen-inducible cre-lox system to selectively delete Dicer from forebrain neurons of adult mice. To further refine this approach, the expression of tamoxifen-inducible CRE recombinase was controlled by the Thy1 promoter. This approach allowed for the selective elimination of Dicer from only a handful of forebrain neurons, thus allowing us to examine the effect of miRNA in a cell-autonomous manner. In these studies, we found that the elimination of miRNA expression decreased neuronal spine density (spines are the locus for synapse formation) and altered neuronal dendritic branching, compared to control mice. By selectively deleting Dicer within the mature brain, we demonstrate that the miRNA class of RNA plays an important role in the regulation of neuronal structure, and, by implication, neuronal function. Given that the structure of a neuron mediates its ability to communicate with other cells and that memory and information processing in the mature nervous system are dependent on activation within a distributed neural network, miRNAs may play an important role in normal cognitive activity.A three-year embargo was granted for this item.Academic Major: Neuroscienc