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| Dr. Smith's Research Description |
 (Click Image to View) Seizure activity alters agrin gene expression |
 (Click Image to View) Agrin-deficient neurons form functional synapses |
 (Click Image to View) Evidence of a neuronal receptor for agrin |
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Research Approach The long term goal of my research is to understand the cellular interactions that control the formation and maintenance of chemical synapses. At the neuromuscular junction, an extracellular matrix protein called agrin triggers differentiation of the postsynaptic apparatus in the muscle fiber. To learn more about agrin's role in synapse formation we have focussed on two questions:
Using a single cell PCR technique, we have demonstrated that developmental changes in the pattern of alternatively spliced agrin mRNAs in the ganglion reflect cell specific differences in agrin expression between different classes of neurons and non-neuronal cells. Other experiments demonstrate that agrin expression by neurons in the ganglion is dependent on target tissue interactions. Consistent with this observation, both the level of agrin mRNA expression and pattern of alternative splicing in PC12 cells are regulated by nerve growth factor. Agrin is also present in many populations of neurons in the rodent brain, where the highest levels of expression during development coincide with periods of synapse formation. The observation that seizure activity influences agrin gene expression suggests further a role for agrin in the activity dependent changes in neuronal circuitry that underlie learning and memory. Surprisingly, however, mutation of the agrin gene which disrupts neuromuscular synapse formation has no apparent effect on neuron-neuron synaptogenesis. As a first step towards identifying what if any function agrin might serve in the CNS we asked which cells in brain respond to agrin. Using expression of the immediate early gene c-fos as a reporter we have established the existence of an agrin receptor on cortical and other CNS neurons. This neuronal receptor for agrin is distinct from that which mediates agrin's effects in skeletal muscle. Experiments are currently underway to identify the gene for this novel agrin receptor, facilitating its analysis using molecular genetics. |
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