miRNAs have emerged as a powerful class of conserved noncoding RNAs that regulate gene expression post-transcriptionally and play critical roles in numerous aspects of development. Numerous miRNAs are expressed at high levels in the nervous system, where they regulate neural development and synaptic plasticity. Impaired expression of miRNAs are implicated in several neurological diseases. Recent studies have identified a few miRNAs that are localized to dendrites in vitro, and in one case, shown to regulate dendritic mRNA translation important for spine development. However, the identity of miRNAs localized to dendrites in vivo is unknown. Axonal miRNAs may regulate local protein synthesis underlying axon guidance, however, the identity of specific miRNAs within axons is unknown so far. We hypothesize that the levels of specific miRNAs within dendrites and axons can be regulated by neuronal activity and receptor signaling pathways to influence the regulation of local protein synthesis important for neuronal development. A major limitation of current technology is that it is unable to quantify changes in miRNA expression in neuronal processes. This project will develop and apply new technology that is capable to identify and quantify novel miRNAs within dendrites and axons.
In aim -1, we will quantify miRNA localization in dendrites of cultured hippocampal and striatal neurons in response to neuronal activity and activation of neurotrophin, glutamate and dopamine receptors. GFP and luciferase reporters will be used to assess the role of a few candidate miRNA in the regulation of dendritic protein synthesis.
In aim -2, we will use similar approaches to identify and assess the role of axonal miRNAs in the regulation of local protein synthesis underlying signaling by axon guidance factors. These studies will advance our understanding of the critical importance played by miRNAs in local protein synthesis underlying synaptic plasticity and axon guidance, which may be altered in disease states, including mental retardation, autism and drug addiction. The quantitative assays developed will be broadly applicable to quantify miRNA expression in models of neurological disease and drug addiction. This research has the potential to lead to the identification of new therapeutic strategies that involve manipulation of miRNAs.
This research will advance our understanding of the critical importance played by miRNAs in local protein synthesis underlying neuronal development, which may be altered in disease states, including drug addiction. The quantitative assays developed will be broadly applicable to quantify miRNA expression in models of neurological disease and drug addiction. This research has the potential to lead to the identification of new therapeutic strategies that involve manipulation of miRNAs.
| Han, Liang; Wen, Zhexing; Lynn, Rachel C et al. (2011) Regulation of chemotropic guidance of nerve growth cones by microRNA. Mol Brain 4:40 |
| Muddashetty, Ravi S; Nalavadi, Vijayalaxmi C; Gross, Christina et al. (2011) Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation, and mGluR signaling. Mol Cell 42:673-88 |
| Gross, Christina; Nakamoto, Mika; Yao, Xiaodi et al. (2010) Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome. J Neurosci 30:10624-38 |
