Oligodendrocyte precursor cells count time but not cell divisions before differentiation

Abstract

During vertebrate development, many types of precursor cell divide a limited number of times before they stop and terminally differentiate. It is unclear what limits cell proliferation and causes the cells to stop dividing when they do. The stopping mechanisms are important as they influence both the number of differentiated cells generated and the timing of differentiation. We have been studying the 'stopping' problem in the oligodendrocyte call lineage [1,2], which is responsible for myelination in the vertebrate central nervous system. Previous studies demonstrated that the proliferation of oligodendrocyte precursor cells isolated from the developing rat optic nerve is limited by an intrinsic 'clock' mechanism [3], which consists of two components: a counting mechanism that counts time or cell divisions, and an effector mechanism that arrests the cell cycle and initiates cell differentiation when the appropriate time is reached [4,5]. In the present study, we address the question of whether the counting mechanism operates by counting cell divisions. We show that precursor cells cultured at 33 °C divide more slowly but stop dividing and differentiate sooner, after fewer cell divisions, than when they are cultured at 37 °C, indicating that the counting mechanism does not count cell divisions but measures time in some other way. In addition, we show that the levels of the cyclin-dependent kinase inhibitor p27(Kip1) (p27) rise faster at 33 °C than at 37 °C, consistent with previous evidence [6] that the accumulation of p27 may be part of the counting mechanism.