Hart, Ian Kirkland; (1991) Studies on the control of oligodendrocyte differentiation in vitro. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The question of why many types of cells stop dividing and differentiate in the continuing presence of growth factors is a fundamental one in animal development. In the rat optic nerve, bipotential 0-2A progenitor cells give rise to oligodendrocytes and type-2 astrocytes on a precise schedule. Previous studies suggest that platelet-derived growth factor (PDGF) plays an important part in timing oligodendrocyte development and that the timing of oligodendrocyte differentiation is secondary to an intrinsic timing mechanism that controls when 0-2A progenitor cells become mitotically unresponsive to PDGF (Raff et al., 1988). This thesis examines the molecular basis of this intrinsic timing mechanism in 0-2A progenitor cells in vitro and looks at the relationship between mitosis and oligodendrocyte differentiation in vivo. 0-2A progenitor cells have a PDGF receptors, suggesting that these cells respond directly to PDGF. The receptors are initially retained when progenitor cells stop dividing in vitro and differentiate into oligodendrocytes. This indicates that receptor loss is not the reason that progenitor cells become mitotically unresponsive to PDGF. Many 0-2A progenitor cells, and newly formed oligodendrocytes which are no longer mitotically responsive to PDGF, show an increase in cytosolic Ca2+ in response to PDGF. A combination of a Ca2+ ionophore plus a phorbol ester mimics the effect of PDGF, both in stimulating 0-2A progenitor cell division and in reconstituting the normal timing of oligodendrocyte differentiation in culture, whereas the same drug combination does not stimulate newly formed oligodendrocytes to proliferate. These findings suggest that at least one reason why newly formed oligodendrocytes do not respond mitotically to PDGF is that there is a block or deficiency downstream from some of the early intracellular events that follow activation of the PDGF receptor. PDGF increases the expression of Fos and Jun in newly formed oligodendrocytes in vitro, suggesting that at least one intracellular signalling pathway to the nucleus is activated by PDGF in these cells even though PDGF does not stimulate them to synthesize DNA. 0-2A progenitor cells in the developing optic nerve, like those in optic nerve cultures, usually stop synthesizing DNA at least 6-12 hours before they express galactocerebroside, an early surface marker of differentiated oligodendrocytes, suggesting that in vivo differentiation follows loss of mitotic responsiveness, just as it does in vitro.

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