Chris Pröschel | PubMed Health

PubMed2004

Getting a GR(i)P on oligodendrocyte development.

One of the most extensively studied of mammalian cells is the oligodendrocyte, the myelin-forming cell of the central nervous system. The ancestry and development of this cell have been studied with every approach utilized by developmental biologists. Such detailed efforts have the potential of providing paradigms of relevance to those interested in analyzing the ancestry and development of any cell type. One of the striking features of studies on the development of oligodendrocytes is that different analytical approaches have led to strikingly different theoretical views regarding the ancestry of these cells. On one extreme is the hypothesis that the steps leading to the generation of oligodendrocytes begin with the generation of a glial-restricted precursor (GRP) cell from neuroepithelial stem cells. GRP cells are thought to be capable of giving rise to all glial cells (including oligodendrocytes and multiple astrocyte populations), but not to neurons, a process that appears to require progression through further stages of greater lineage restriction. On the other extreme is the hypothesis that oligodendrocytes are derived from a precursor cell that generates only motor neurons and oligodendrocytes, with astrocytes being generated through a separate lineage. In this review, we critically consider the various contributions to understanding the ancestry of oligodendrocytes, with particular attention to the respective merits of the GRP cell vs. the motor neuron-oligodendrocyte precursor (MNOP) cell hypothesis. We draw the conclusion that, at present, the strengths of the GRP cell hypothesis outweigh those of the MNOP hypothesis and other hypotheses suggesting oligodendrocytes are developmentally more related to motor neurons than to astrocytes. Moreover, it is clear from existing data that, following the period of motor neuron generation, the major glial precursor cell in the embryonic spinal cord is the GRP cell, and that multiple previous studies on the earliest stages of oligodendrocyte generation in the developing spinal cord have been focused on a differentiation stage of GRP cells.

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PubMedDate not supplied

Redox regulation of precursor cell function: insights and paradoxes.

Studies on oligodendrocytes, the myelin-forming cells of the central nervous system, and on the progenitor cells from which they are derived, have provided several novel insights into the role of intracellular redox state in cell function. This review discusses our findings indicating that intracellular redox state is utilized by the organism as a means of regulating the balance between progenitor cell division and differentiation. This regulation is achieved in part through cell-intrinsic differences that modify the response of cells to extracellular signaling molecules, such that cells that are slightly more reduced are more responsive to inducers of cell survival and division and less responsive to inducers of differentiation or cell death. Cells that are slightly more oxidized, in contrast, show a greater response to inducers of differentiation or cell death, but less response to inducers of proliferation or survival. Regulation is also achieved by the ability of exogenous signaling molecules to modify intracellular redox state in a highly predictable manner, such that signaling molecules that promote self-renewal make progenitor cells more reduced and those that promote differentiation make cells more oxidized. In both cases, the redox changes induced by exposure to exogenous signaling molecules are a necessary component of their mode of action. Paradoxically, the results obtained through studies on the oligodendrocyte lineage are precisely the opposite of what might be predicted from a large number of studies demonstrating the ability of reactive oxidative species to enhance the effects of signaling through receptor tyrosine kinase receptors and to promote cell proliferation. Taken in sum, available data demonstrate clearly the existence of two distinct programs of cellular responses to changes in oxidative status. In one of these, becoming even slightly more oxidized is sufficient to inhibit proliferation and induce differentiation. In the second program, similar changes enhance proliferation. It is not yet clear how cells can interpret putatively identical signals in such opposite manners, but it does already seem clear that resolving this paradox will provide insights of considerable relevance to the understanding of normal development, tissue repair, and tumorigenesis.

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