The Logic of Neural Cell Lineage Restriction: Neuropoiesis Revisited

The neurons and glia of the central and peripheral nervous systems (CNS and PNS) are thought to derive from initially multipotent, self-renewing stem cells. These cells have been assumed to undergo a sequence of lineage restrictions, in which they first generate committed neuronal or glial progenitors, which then generate different subtypes of neurons and glia, respectively. Evidence presented here from both the PNS and CNS suggests that, although the fundamental concept of sequential lineage restriction is likely to be correct, the logic of such restrictions is not the one widely assumed to be true. Rather, we suggest that multipotent progenitors of neurons and glia become fate-restricted to generating different subtypes of neurons and glia, before they become committed to neuronal and glial fates. This pattern of lineage restriction events can be explained in terms of the molecular mechanisms that control the neuron vs. glia fate choice and of those that specify neuronal and glial subtype identity. An outstanding question raised by these studies is the relationship of such multipotent but subtype-restricted progenitor cells in vivo to self-renewing CNS stem cells that have been described in vitro.