In the belly of the microglia: towards a quantitative dynamic understanding of neuronal degradation in vivo

During brain development, neuronal precursors are generated in great excess. Only those that make functional connections survive, while the vast majority undergoes apoptosis and is eliminated by microglia. It is clear that effective processing of these neurons is essential, but the underlying cellular mechanisms are poorly understood. Using living fish embryos, we showed that neuronal cargo processing depends on the shrinkage and packaging of microglial phagosomes into a unique cellular compartment, the gastrosome, with distinct molecular and ultrastructural characteristics. Loss of the transporter Slc37a2 blocks phagosomal shrinkage, resulting in the expansion of the gastrosome and the dramatic bloating of the cell. This, in turn, affects the ability of microglia to phagocytose and migrate toward brain injuries. Thus, mechanisms must exist in microglia to regulate uptake and maintain these cells' surface area and functional morphology. We have discovered that the movement of the centrosome provides one such mechanism. Translocation of this organelle towards forming phagocytic cups favors their closure and subsequent neuronal removal.  Thus, the centrosome appears to limit the rate of neuronal engulfment, and its targeted movement is sufficient to polarize microglia and promote neuronal uptake. These findings provide powerful ways to affect microglia and modulate the impact that these cells have in the context of many neurodegenerative disorders.

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