Hart I K, Richardson W D, Bolsover S R, Raff M C
Biology Department, University College London, United Kingdom.
J Cell Biol. 1989 Dec;109(6 Pt 2):3411-7. doi: 10.1083/jcb.109.6.3411.
In the rat optic nerve, bipotential O-2A progenitor cells give rise to oligodendrocytes and type 2 astrocytes on a precise schedule. Previous studies suggest that PDGF plays an important part in timing oligodendrocyte development by stimulating O-2A progenitor cells to proliferate until they become mitotically unresponsive to PDGF, stop dividing, and differentiate automatically into oligodendrocytes. Since the loss of mitotic responsiveness to PDGF has been shown not to be due to a loss of PDGF receptors, we have now examined the possibility that the unresponsiveness results from an uncoupling of these receptors from early intracellular signaling pathways. We show that (a) although PDGF does not stimulate newly formed oligodendrocytes to synthesize DNA, it induces an increase in cytosolic Ca2+ in these cells; (b) a combination of a Ca2+ ionophore plus a phorbol ester mimics the effect of PDGF, both in stimulating O-2A progenitor cell division and in reconstituting the normal timing of oligodendrocyte differentiation in culture; and (c) the same combination of drugs does not stimulate newly formed oligodendrocytes to proliferate, even in the presence of PDGF or dibutyryl cAMP. The most parsimonious explanation for these results is that O-2A progenitor cells become mitotically unresponsive to PDGF because the intracellular signaling pathways from the PDGF receptor to the nucleus are blocked downstream from the receptor and some of the early events that are triggered by receptor activation.
在大鼠视神经中，双潜能O-2A祖细胞按照精确的时间表分化为少突胶质细胞和2型星形胶质细胞。先前的研究表明，血小板源性生长因子（PDGF）通过刺激O-2A祖细胞增殖，直至它们对PDGF不再产生有丝分裂反应、停止分裂并自动分化为少突胶质细胞，从而在少突胶质细胞发育的时间调控中发挥重要作用。由于已表明对PDGF有丝分裂反应的丧失并非由于PDGF受体的丧失，我们现在研究了这种无反应性是否是由于这些受体与早期细胞内信号通路解偶联所致。我们发现：（a）尽管PDGF不刺激新形成的少突胶质细胞合成DNA，但它能诱导这些细胞胞质Ca2+增加；（b）钙离子载体与佛波酯的组合模拟了PDGF的作用，既能刺激O-2A祖细胞分裂，又能在培养中重建少突胶质细胞分化的正常时间进程；（c）即使存在PDGF或二丁酰cAMP，相同的药物组合也不会刺激新形成的少突胶质细胞增殖。对这些结果最简洁的解释是，O-2A祖细胞对PDGF产生有丝分裂无反应是因为从PDGF受体到细胞核的细胞内信号通路在受体下游以及受体激活引发的一些早期事件处被阻断。
