Control by extracellular signals

Although the timer is cell-intrinsic, it requires signals from other cells to operate normally. It depends on PDGF, for example, the main mitogen for OPCs. The

PDGF is probably provided by astrocytes and is the only mitogen that on its own can stimulate purified OPCs in culture to proliferate (Ibarrola et al 1996). Moreover, in mice in which the PDGFA gene has been inactivated, OPCs do not proliferate and very few oligodendrocytes develop (Fruttiger et al 1999). When OPCs are cultured on their own with survival signals but without PDGF, they prematurely stop dividing and differentiate (Barres et al 1994, Temple & Raff 1985).

The timer is also regulated by thyroid hormone (TH), which has been known for many years to influence oligodendrocyte development. In developing animals that are hypothyroid, for example, myelination is greatly delayed (Dussault & Ruel 1987, Rodriguez-Pena et al 1993), whereas in developing animals that are hyperthyroid, myelination is accelerated (Walters & Morell 1981). The evidence that TH influences the intrinsic timer in OPCs comes from experiments that compare the behaviour of purified OPCs cultured in PDGF in the presence or absence of TH (Barres et al 1994). When OPCs purified from the optic nerve of postnatal day 8 (P8) rats are grown at clonal density in PDGF and TH, the cells divide a maximum of eight times before they stop and differentiate; in the absence of TH, by contrast, most of the cells tend to keep dividing and do not differentiate. If the OPCs are cultured at clonal density in PDGF in the absence of TH for 8 days, and then TH is added, most of the cells stop dividing and differentiate within 4 days, suggesting that the cells can measure time in the absence of TH. It seems that the timer consists of at least two components — a counting component that measures time independently of TH and an effector component that is regulated by TH and stops the cell cycle and initiates differentiation when time is up. TH also seems to be required for normal oligodendrocyte development in the optic nerve: hypothyroid rats (Ibarrola et al 1996) and mice (Ahlgren et al 1997) have many fewer oligodendrocytes in their optic nerves at P7. As TH influences the differentiation of many types of vertebrate precursor cells, it may help to coordinate the timing of cell differentiation in tissues throughout the body, just as it co-ordinates the events of amphibian metamorphosis.

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