|DFXR and synaptic tagging in drosophila (fruit flies)
by Jerry Yin, 7/1/2003
My laboratory is interested in the molecular mechanisms of memory formation. We study the Drosophila (fruit fly) and mouse model systems. All animals can form memories that persist for various lengths of time. Long-term memories, which require new proteins to be made in brain cells, enlist cell-wide processes such as gene transcription and translation. While these processes occur in the cell body, most neuroscientists agree that the specificity of neuronal circuits requires changes in the individual synapses that define the circuit. Since mammalian nerve cells can contain thousands of synapses, how are individual synapses targeted when cell-wide changes such as gene expression occur? This problem is a central issue in the field of memory formation. We are trying to test whether FMRP is involved in the molecular mechanism of synaptic specificity. We use genetic and biochemical approaches in fruit flies to address this problem.
It is now clear that one of the major functions that the FMRP protein performs is to bind mRNA molecules in the cell. This binding is probably involved in the transport and regulation of usage (translation) of the mRNA. Recent work in a number of laboratories suggests that some of the mRNAs that the FMRP protein binds to are sent out of the nucleus, the site of their synthesis, to distant regions of the neuron where the sites of memories are likely to be located (synapses). It is likely that neuronal activity at the synapse leads to the usage (translation) of various mRNAs at that synapse only, and that the Fragile X protein is somehow involved in this process. When the Fragile X protein is missing, the mRNA targets that it normally binds to are translated too frequently, and probably at the wrong places, resulting in the dysfunctions associated with the disease.
Our lab is interested in understanding what happens to the Fragile X protein during the process of translation. We hypothesize that in response to neuronal activity, it undergoes modifications, allowing the mRNA targets to be translated at the synapse that was just active. We are searching for these modifications that might modulate the activity of the protein, and are involved in "tethering" it to the active synapse. In addition, we are trying to understand the molecules that might be involved in this "tethering" process.