MicroRNAs (miRNAs) are noncoding RNAs expressed within the genomes of multiple species. Prior work has demonstrated that miRNAs are expressed in developing and adult tissues, and their expression can be constitutive, temporal, ubiquitous, or cell-specific. A new class of negative regulators of expression, miRNAs work by inhibiting translation of target messenger RNAs (mRNAs) via base pairing with mRNA 3'untranslated regions. This process is called RNA interference (RNAi). Since the discovery of RNAi in worms, which was awarded the Nobel prize in physiology or medicine in 2006, studies of naturally occurring RNAi in developing vertebrate organs and in adult animals have revealed their important contribution to cellular phenotypes. Recent work has shown that miRNAs participate in teratogen-mediated changes. We also know that teratogens impair proliferation of neural progenitors. What we do not know, however, is the interface between miRNAs and neural progenitor cell maintenance, proliferation and differentiation. In this proposal we will first use a focused approach to assess how a candidate miRNA, miR-34a, participates in cell fate decisions in neural progenitor cells in culture and in vivo. In additional studies we will ascertain how perturbing miR-34a levels impacts target protein expression.
Two aims are proposed.
In Aim 1 we will use anti-miRs and miRexpression vectors to test how miR-34a impacts neuronal differentiation in loss- and gain- of function experiments, respectively, in vitro and in vivo.
In Aim 2 we will use anti-miRs and miR-expression vectors to test how miR-34a levels effects miR-34a target proteins.
| Boudreau, Ryan L; Jiang, Peng; Gilmore, Brian L et al. (2014) Transcriptome-wide discovery of microRNA binding sites in human brain. Neuron 81:294-305 |
| McLoughlin, H S; Fineberg, S K; Ghosh, L L et al. (2012) Dicer is required for proliferation, viability, migration and differentiation in corticoneurogenesis. Neuroscience 223:285-95 |
| Fineberg, Sarah K; Datta, Poppy; Stein, Colleen S et al. (2012) MiR-34a represses Numbl in murine neural progenitor cells and antagonizes neuronal differentiation. PLoS One 7:e38562 |
| Monteys, Alex Mas; Spengler, Ryan M; Wan, Ji et al. (2010) Structure and activity of putative intronic miRNA promoters. RNA 16:495-505 |
| Fineberg, Sarah K; Kosik, Kenneth S; Davidson, Beverly L (2009) MicroRNAs potentiate neural development. Neuron 64:303-9 |
