How do our brains become wired the way they are? During development nerve cells migrate from their site of origin to their destination and then begin to send out tiny processes to find their synaptic partners. As such these cells and their processes must differentiate appropriate partners from inappropriate targets. The fidelity with which this happens is truly astounding. Neuroscientists have found that molecules outside the cells instruct all the stages of neural development. For example growth factors secreted from other cells instruct nerve cells to adopt the correct fate, diffusible cues inform neurons where potential synaptic partners might be located and cell surface cues can tell them when they have reached their targets.
One organizing force behind all of the distinct molecular cues that instruct neural development is the extracellular matrix (ECM). Extracellular matrices provide trophic and structural support to all tissues during development. Our lab studies how extracellular molecules shape the nervous system. It is well known that the cellular environment is critical for the proper formation and function of neural circuits. We use the genetically amenable nematode, Caenorhabditis elegans, to probe how external cues are sensed by neurons and their targets. Recently our work has focused on a group of molecules that function at synapses that, when defective, result in phenotypes that are similar to Muscular Dystrophies. We have been looking for new mutations that suppress the synapse defects, because these molecules are potential therapeutic targets for MD. As such we have identified a calcium signaling pathway that appears to be conserved from nematodes to vertebrates that acts in our genetic pathway.
A second interest in the lab is how aging changes the ECM and these changes have specific effects on cells. For example, since loss of nidogen results in synaptic defects, if nidogen is not replaced during normal aging, does this loss cause age-related synaptic defects? We are currently cataloging the changes in our known ECM components through normal aging and correlating them with behavioral analyses on neuromuscular system. In the future we will compare the changes in normal animals with those that have defects in known aging circuits to differentiate changes that are inherent in ECM molecules and those that are due to cellular aging.
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