Hall, Anita Caroline; (1999) Platelet-derived growth factor and its alpha-receptor subunit in oligodendrocyte development. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

How the diverse range of cell types seen in the vertebrate central nervous system (CNS) is generated is one of the most intriguing questions in developmental neurobiology. This Thesis concentrates on the development of oligodendrocytes, the myelinating cells of the CNS. There have been several hypotheses as to where in the embryo oligodendrocyte progenitors originate. Accumulating circumstantial evidence suggests that cells expressing platelet-derived growth factor alpha-receptor (PDGFRα+ cells) in the embryonic spinal cord are oligodendrocyte progenitors. In Chapter Three I demonstrate that these PDGFRα+ cells differentiate into oligodendrocytes in vitro, providing direct evidence that oligodendrocytes develop from a discrete group of PDGFRα+ cells in the ventral ventricular zone of the embryonic spinal cord. Further in vitro experiments suggest that PDGFRα+ progenitors are the major or only source of oligodendrocytes within the developing spinal cord. In Chapter Four I demonstrate that PDGFRα+ cells in the embryonic brain are oligodendrocyte progenitors. I describe evidence that suggests that PDGFRα+ oligodendrocyte progenitors originate in the ventral diencephalon and migrate throughout the brain during subsequent development I demonstrate that dorsal forebrain cells, at an age when PDGFRα+ cells are not present, can generate oligodendrocytes in vitro if treated with certain factors. However, it is not clear whether this potential is realised in vivo. In Chapter Five of this Thesis I investigate the roles of the ligands for PDGFRα (PDGF-A and PDGF-B) during oligodendrocyte progenitor development in vivo. By examining PDGF-A and PDGF-B null mice I show that PDGF-AA but not PDGF-BB or PDGF-AB is crucial for PDGFRα+ oligodendrocyte progenitor proliferation in the spinal cord in vivo. Further experiments with transgenic mice demonstrate that the amount of PDGF-AA available to each PDGFRα+ progenitor in vivo controls the length of its cell cycle and; therefore, PDGF-AA availability is one factor that regulates oligodendrocyte progenitor number in vivo.

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