The communications between neurons and glial cells, as well as the ones among different glial cell types (astrocytes, oligodendrocytes, and microglia) are critical for normal nervous system function. The molecular and cellular mechanisms underlying these communications remain largely unknown. Oligodendrocyte-axon unit provides an excellent model to study neuron-glia interactions. Specifically, we are interested in the mechanisms that establish the initial axonal ensheathment by oligodendrocyte processes. Recent work showed that, intriguingly, the nervous system is inadequately myelinated; only a small portion of axons are myelinated even in the adulthood. In addition, there are also many unmyelinated segments along the myelinated axons. How do oligodendrocytes choose subsets of axons to myelinate? Is there any selectivity between axons and individual oligodendrocyte’s processes (20-30 per oligodendrocyte) that will myelinate these axons? What are the mechanisms governing the regional and temporal specificity across diverse brain regions? To address these questions, we have established primary oligodendrocyte-neuron co-culture platform as well as multiple in vivo murine systems, including the optic nerve (fully myelinated), the cortex (partially myelinated), and the cerebellum molecular layer (no myelination).