Timing cellcycle exit and differentiation in oligodendrocyte development

Martin Raff, Jim Apperly, Toru Kondo, Yasuhito Tokumoto and Dean Tang

MRC Developmental Neurobiology Programme, MRC Laboratory for Molecular Cell Biology and the Biology Department, University College London, London WC1E 6BT, UK

.Abstract. During animal development many cells permanently stop dividing and terminally differentiate. For the most part, the mechanisms that control when the cells exit the cell cycle and differentiate are not known. We have been studying the mechanisms in the oligodendrocyte cell lineage. Studies of oligodendrocyte precursor cells (OPCs) in culture suggest that each OPC has a built-in timing mechanism that helps determine when the cell stops dividing and differentiates. This intrinsic timer consists of at least two components — a timing component, which measures elapsed time, and an effector component, which stops cell division and initiates differentiation at the appropriate time. The timer seems to involve both transcriptional and post-transcriptional mechanisms, with some proteins progressively increasing and others progressively decreasing over time.

2001 The cell cycle and development. Wiley, Chichester (Novartis Foundation Symposium 237) p 100-112

Most mammalian cell types develop from precursor cells that divide a limited number of times before they stop and terminally differentiate. In no case do we understand why the cells stop dividing when they do. The stopping mechanisms are important because they determine how many differentiated cells are produced and when differentiation begins. We have been studying the stopping mechanism in oligodendrocyte precursor cells (OPCs) isolated from the developing optic nerve of rats and mice.

The optic nerve contains the axons of retinal ganglion cells and two major classes of macroglial cells — astrocytes and oligodendrocytes. The oligodendrocytes myelinate the axons, while the astrocytes provide structure and help control the environment in the nerve. The astrocytes develop from the neuroepithelial cells of the optic stalk, the primordium of the optic nerve, whereas the oligodendrocytes develop from OPCs that migrate into the developing optic nerve from the brain just before birth (Ono et al 1997, Small et al 1987). The

OPCs divide a limited number of times in the nerve and then terminally differentiate into postmitotic oligodendrocytes. The first OPCs stop dividing and differentiate on the day of birth (Miller et al 1985), and new ones do so over the next six weeks (Barres et al 1992). We have studied the mechanisms that control when the OPCs stop dividing and differentiate in culture and find that both cell-intrinsic programmes and extracellular signals are involved.

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