The Last Shall Not Be First The Ordered Generation of Progeny from Stem Cells

The demonstration that information required for the generation of neurons before glia is intrinsic to individual stem cell–derived clones poses the question of mechanism. One possibility is that there is a clock intrinsic to stem cells that determines when daughter cells will be Discussions of CNS stem cell biology often leave the specified to adopt neuronal fates and when they will impression that neural stem cells persist throughout life adopt glial fates (see figure, panel A). But as acknowl-and that stem cells from the adult cortex are the same edged by Temple and colleagues, there are a number of variations on this theme that would allow environmental as the stem cells that build the CNS during fetal develop-signals or feedback mechanisms to also modulate the ment. In fact, the properties of CNS stem cells have process. For example, it is possible that stem cells are not yet been carefully compared throughout ontogeny; programmed to generate neurons first but that a feed-however, by analogy to stem cells of the immune system, back signal from the neurons to the stem cells induces we would expect neural stem cells to change their prop-glial specification (see figure, panel B). In addition to erties over time. Fetal hematopoietic stem cells (HSC) the order of specification, differences in the proliferative have a broader developmental potential than adult HSCs behavior of restricted neuronal and glial progenitors may in that they are able to make certain classes of T cells also contribute to the generation of neurons followed that are not made by adult HSCs, even when the adult by glia. For instance, neuronal and glial specification HSCs are transplanted into the fetal environment (Ikuta could occur at the same time but neuroblast differentia-et al., 1990). Apart from such overt changes in potential, tion may occur much faster than glioblast differentiation HSCs also change their properties in more subtle ways (see figure, panel C). The important point is that the with age. Adult HSCs are less able to produce certain timing of differentiation may be regulated in part by types of B cells and erythrocytes than fetal HSCs (Wood controls acting on the proliferation of restricted progeni-et al., 1985; Kantor et al., 1992). Even the cell cycle status tors as well as by controls on stem cell function. Thus, and proliferative potential of HSCs change throughout while a program that causes neurons to differentiate ontogeny. Therefore, in considering …