Research SummaryDevelopment and repair of nervous sytem
Our lab is interested in understanding how our brain develops and repairs when there is abnormality such as injury and diseases. Towards this goal we use a combination of molecular genetics, biochemistry and quantitative in vivo imaging in Caenorhabditis elegans. To address these questions we focused our attention to the regulation of microtubule cytoskeleton in neuron.
Microtubule cytoskeleton is the basis of the polarized structure of neuron. Stabilization of microtubule determines neuronal polarity. Since microtubule stability is inversely related to microtubule depolymerization, neuronal polarization must be accompanied by the protection of microtubules from microtubule destabilization players. It is not clear yet, what regulates microtubule-depolymerizing enzymes directly or protects microtubules from depolymerization during the establishment of neuronal polarity. Using genetic screening we are identifying candidates that regulates neuronal microtubules during the establishment of neuronal polarity. This study deals with the long-standing question in neuronal cell biology that how axonal microtubules are stabilized without the influence of centrosome. This will also help us elucidate the mechanisms by which polarity cues instruct structural components of neuron to build polarity.
In order to understand how microtubules are maintained after axon development, I will focus on posttranslational modification mechanism of tubulin. First I will analyze the mechanisms regulating tubulin detyrosination in vivo, using a forward genetic screen for suppressors of a tubulin tyrosine ligase mutant and test the molecular function of the suppressors using biochemical assay. I will study how synaptogenesis and synaptic plasticity pathways regulate tubulin posttranslational modifications in mature and remodeling neural circuit respectively.
Finally, I will ask, how neuronal cytoskeleton is regulated by axonal injury. This will allow us to test further whether by changing the parameters of microtubule dynamics one can prevent degeneration or promote regeneration. Overall, identifying genetic determinants of neuronal response to injury should help inform therapeutic strategy for the treatment of nervous system abnormalities and injuries in humans