p600 Links Microtubules to the Endoplasmic Reticulum
There is an increasing body of literature pointing to cytoskeletal proteins as spatial organizers and interactors of organelles. A few years ago, we identified protein 600 (p600) as a novel microtubule-associated protein (MAP) developmentally regulated in neurons. We discovered that p600 exhibits the unique ability to interact with the endoplasmic reticulum (ER), a compartment critical for Ca2+ signaling and homeostasis (Shim et al., Journal of Neuroscience 2008). Loss of p600 function experiments revealed that not only p600 is important for neuronal morphogenesis and integrity but also for ER transport. For instance, p600-depleted migrating neurons in the developing neocortex display thin, crooked, and “zigzag” leading process with very few ER membranes. Thus, p600 constitutes the only known MAP to associate with the ER in neurons, and this interaction may impact on multiple Ca2+-dependent cellular processes ranging from neuronal development to neuronal maturation and plasticity.
Along these lines, we later found that p600 associates with another MAP – called Ndel1 - to impact spindle orientation and cell fate choice of neural progenitors in the neocortex (Belzil et al., Biology Open 2014). As we contributed to the discovery that p600 null mice are embryonic lethal (Nakaya et al., PLOS ONE 2013; Tasaki et al., PNAS 2013), we used cultured hippocampal neurons to dissect the functions of p600 in mature neurons. We found that in active neurons p600 preserves cell structure upon Ca2+ dyshomeostasis induced by glutamate treatment via direct binding to Calmodulin and in a microtubule-independent manner, or by stabilizing microtubules upon direct depolarization (Belzil et al. Journal of Biological Chemistry 2014; Belzil et al., Cell Mol Biol Letters 2014). Taken together, our research advances our understanding of the fundamental roles of the p600 in neuronal development, survival and maintenance. The works are summarized in a review article (Parsons et al., Cellular and Molecular Life Sciences 2015).