Lineage and Development

Most developmental studies of oligodendroglial lineage and development have been conducted in rodent models due to difficulty in culturing human oligoden-drocytes. The maturation of oligodendrocyte precursors into mature oligodendrocytes is characterized by a distinct temporal expression of cell surface receptors and response to different growth factors. In mammals, oligodendrocytes originate from multipotential neural stem cells derived from the neuroepithe-lium of the developing CNS. In the adult brain, mature

Figure 3 Immunofluorescent staining of a mammalian oligodendrocyte. Stained for Gal-C, a galactocerebroside expressed during the final stages of oligodendroglial development. Note the highly branched processes and intense staining of the cell membrane.

oligodendrocytes are distributed throughout the white and gray matter. In the developing CNS, however, induction of oligodendroglial precursors occurs in spatially restricted areas. Chemical factors released into localized areas of the extracellular environment can initiate changes in morphology and expression of growth factor receptor mRNA. In rodent studies, it is thought that the precursors are initially restricted to the ventral ventricular zone of the developing neural tube. The notochord and surrounding floor plate may release factors such as sonic hedgehog, which results in migration of the precursors dorsally and radially to populate the white matter. Furthermore, oligodendro-cyte precursors located in the developing midbrain and forebrain may migrate into the thalamus and hypothalamus later in development, as well as to more dorsal regions of the cerebral cortex.

Induction of the oligodendrocyte progenitors from neuroepithelial stem cells in discrete locations must be followed by an active and large-scale migration throughout the CNS in order to myelinate all the white matter tracts. The cellular terrains or soluble factors utilized during this long-distance migration are unknown. The traveling precursors may interact with radial glial cells or may even utilize axons to guide them to their final destination. The oligodendrocyte precursors do possess a variety of integrin receptors, which may play important roles in migration and differentiation over various extracellular matrix components.

Extensive proliferation occurs in the white matter, and the expansion of the oligodendrocyte population is most likely regulated by a variety of growth factors. Once sufficient progenitor populations have been achieved, proliferation is downregulated and shifted toward differentiation. Again, maturation of the oligodendrocytes is highly influenced by growth factors and hormones. As the precursors mature, they will lose their motility and various cell surface receptors. Table II summarizes the proposed stages of oligoden-droglial development and progressive changes in cell surface markers, morphology, and motility. Terminal differentiation of oligodendrocyte precursors and initiation of myelination requires dramatic and highly coordinated changes in the pattern of gene expression. The molecular mechanism by which oligodendrocyte-specific gene expression is regulated is most likely due to the combined action of multiple transcription factors. These include members of the homeodomain proteins in undifferentiated oligodendrocytes and zinc finger proteins in mature oligodendrocytes. Oligoden-droglial survival factors secreted at the final destination induce the synthesis of myelin-specific mRNA, such as myelin basic protein (MBP) and proteolipid protein (PLP). MBP is actually a family of seven protein isoforms produced from a single gene by alternative splicing. Little is known about the precise structure of MBP in its native environment, although it is believed that the proteins are self-associating and may exist in an oligomeric form at the cell membrane.

Table II

Oligodendroglial Development"

Stage

Specific cell surface marker

Morphology

Motility

Preoligodendroglia, oligodendrocyte precursor (OP)

PDGFRa, O4 immunoreactivity

Highly motile

Immature oligodendrocyte

O1 immunoreactivity

Mature oligodendroctye

Less motile

None

"Abbreviations used: PDGFRa, platelet-derived growth factor receptor alpha; O4, antibody that recognizes cell surface constituents specific for oligodendrocyte precursors; O1, antibody against galactosylcerebroside; CNP, 2',3'-cyclic nucleotide 3'-phosphotidase; PLP, proteolipid protein; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein.

PLP is the most abundant protein in CNS myelin and also has alternative splice variants. With several transmembrane domains, functional studies have implicated a role of PLP as an ion channel.

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