Dividing glial cells maintain differentiated properties including complex morphology and functional synapses

Abstract

It is generally believed that dividing cells gain complex features of differentiation only after exiting the cell cycle because cell division and differentiation are both under such tight regulation that their coexistence is deemed unlikely. As the major proliferating cell type in the mammalian CNS, NG2 glial cells (NG2 cells) account for 5-8% of the glial cell population and form synaptic contacts with neurons. Here we report that NG2 cells divide while maintaining their differentiation, including morphological features, such as the elaboration of multiple complex cellular processes and physiological features including active glutamatergic and GABAergic synaptic responses. Not only do NG2 cells continue to receive excitatory and inhibitory synaptic inputs as they undergo mitosis, a subpopulation of dividing NG2 cells can fire action potentials upon depolarization, thereby revealing that these dividing NG2 cells retain voltage-gated ion channels as well as transmitter receptors for signal processing. These findings provide a clear counterexample of the widely perceived incompatibility between cell division and differentiation.action potential ͉ differentiation ͉ NG2 cells ͉ proliferation ͉ mitosis G lial cells constitute 90% of the cells in our brain and have been classified as astrocytes, oligodendrocytes, and microglia (1). NG2 glial cells (NG2 cells), previously known as ''protoplasmic'' astrocytes on the basis of their morphology in the adult CNS (2), have also been described as oligodendrocytetype-2 astrocytes (O2A) (3), oligodendrocyte precursor cells (4), ''complex glia'' (5), or polydendrocytes (6). NG2 cells are the only glial cells that express the chondroitin sulfate proteoglycan NG2, which not only provides the namesake but also serves as a cell marker for NG2 cells (2, 7). Whereas some NG2-expressing cells can generate oligodendrocytes and astrocytes at early developmental stages in vivo (8), there are many NG2 cells in the adult brain after the completion of myelination (4). Moreover, NG2 expression in the adult brain does not overlap with the expression of markers for other glial cell types (9) nor do NG2 cells express immature cell markers including nestin and DCX. Importantly, NG2 cells receive synaptic inputs from neurons (10-14), and the neuron-NG2 glia synapses can undergo activitydependent modification analogous to long-term potentiation (11), a hallmark of the cellular mechanism underlying learning and memory (15). NG2 cells also make contact with nodes of Ranvier (16) in the white matter and hence are capable of responding to or modulating neuronal activity in a manner perhaps similar to the function of astrocytes (17). Given the unique morphological, physiological, and functional properties of NG2 cells, which are widely distributed in the adult brain, they are now recognized as a distinct, differentiated, macroglial cell population (18,19).NG2 cells retain the ability to proliferate throughout life (9). They represent the main population of dividing cells and account for Ϸ70% of BrdU inc...

Postnatal Switch from Synaptic to Extrasynaptic Transmission between Interneurons and NG2 Cells

“…Synaptic transmission of NG2 cells is an attractive candidate for controlling proliferation and differentiation of these cells in an activity-dependent manner and thus for influencing CNS myelination, although direct evidence is lacking. Indeed, proliferating NG2 cells keep their synapses and transfer them to their progeny during cell division (Kukley et al, 2008;Ge et al, 2009). In addition, there is an increasing axonal glutamatergic "synaptic-like" activity in NG2 cells of the corpus callosum that evolves in parallel with the maturation of the white matter tract (Ziskin et al, 2007).…”

Development of a glial network in the olfactory nerve: role of calcium and neuronal activity

“…We do not know if the cells that were dividing were actively migrating, as has been reported to occur in NG2 glial cells of mice (Ge et al, 2009), or if they were simply paused, or had completed their migration.…”

“…In the moth, which has a substantive nerve comprising more than 300,000 axons (Sanes and Hildebrand, 1975;Oland and Tolbert, 1989), dividing glial cells also are found throughout the nerve as the population is migrating toward the brain. We do not know if glial cells are proliferating while migrating, as has been shown in NG2 glial cells of mice (Ge et al, 2009) (Silies et al, 2007;Murakami et al, 2007), but elsewhere this part of the process simply is poorly understood, even in systems where good progress has been made in identifying key signaling pathways that initiate and maintain glial migration (Klambt, 2009).…”

Synantocytes: the fifth type of glia? In comparison with astrocytes.

“…Moreover, they can occur by synapses becoming integral component, taking part in synaptic signalization [4,6,14]. In hippocampus synantocyte contacts fewer than 20 synapses on average, in comparison with astrocyte which forms about 100.000 of them [15][16][17]. Under electron microscope one observed that axon buttons containing fewer synaptic vesicles form junctions with synantocyte processes in which there is a lack of postsynaptic density [2].…”