Yu, Wei-Ping; (1995) Glial cell lineages in the developing central nervous system. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Glial cells far outnumber neurons in the central nervous system (CNS), yet relatively little is known about where they originate during development or how they subsequently distribute themselves throughout the CNS. In this Thesis I report the results of in situ hybridization experiments with a probe for mRNA transcripts encoding the "myelin" protein 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP); these experiments strongly suggest that the precursors of oligodendrocytes, the myelinating cells of the CNS, originate at a discrete locus in the ventral ventricular zone of the embryonic day 14 (E14) rat spinal cord. Similar experiments with a probe to proteolipid protein (PLP) mRNA, another myelin gene product, indicate that this gene is expressed by a different group of neuroepithelial precursors, not necessarily related to the oligodendrocyte lineage, in the ventral-most ventricular zone abutting the floor plate. The notochord and floor plate, at the ventral midline of the developing spinal cord, act as organizing centres for the developing spinal cord. For example, in the absence of a notochord/floor plate complex, motor neurons (MNs) do not develop, and an extra pool of MNs can be induced in a dorsolateral position by grafting a supernumerary notochord to one side of the embryonic neural tube. Because the available markers for MNs label only the post-mitotic cells outside of the ventricular zone, it has not been possible to determine whether floor plate-derived signals act by influencing the differentiation fates of post-mitotic, pluripotent progenitor cells after they have migrated away from the ventricular zone, or whether they act by pre-specifying the future fates of neuroepithelial precursors while they still reside within the ventricular zone. I addressed this question by examining the development of the oligodendrocyte lineage in Danforth's Short Tail (Sd) mutant mice, which lack a notochord and floor plate in caudal regions of the spinal cord. I found that, in these mice, oligodendrocyte precursors never appeared at the ventricular surface, supporting the view that the role of the floor plate is to commit proliferating neuroepithelial cells to particular future cell fates. I also examined the role of fibroblast growth factor (FGF) in the development of the oligodendrocyte lineage, by identifying the FGF receptor subtypes present on oligodendrocyte progenitor cells. I found that these cells express a cocktail of receptors including FGFR-1, FGFR.-2 and FGFR-3 in vitro. During an in situ hybridization survey of FGFR expression in the developing CNS, I identified two foci of FGFR-3-expressing cells in the ventricular zone of the E16 spinal cord. These groups of ventricular precursors appear to generate migratory cells that spread throughout the cross section of the cord between E16 and El8. By culturing embryonic spinal cord cells in vitro and performing combined immunocytochemistry and in situ hybridization with probes for glial fibrillary acidic protein (GFAP) and FGFR-3, I showed that many of the FGFR-3-expressing cells give rise to astrocytes in vitro. Thus, two different subclasses of glia, oligodendrocytes and astrocytes, appear to originate at different loci in the ventricular zone of the neural tube. These data support the general conclusion that the ventricular zone is a mosaic of different, specialized precursor cells, each dedicated to the production of one, or a subset, of neural cell types.

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