Ross M E, Carter M L, Lee J H
Department of Neurology, University of Minnesota, Minneapolis 55455, USA.
J Neurosci. 1996 Jan;16(1):210-9. doi: 10.1523/JNEUROSCI.16-01-00210.1996.
Although the regulation of proliferation and differentiation during brain development has long been considered to be interrelated, the mechanisms that coordinate the control of cell division and histogenesis are poorly understood. The cell cycle is a dynamic process that is governed by the concerted action of numerous cell cycle regulatory proteins in response to signals both intrinsic and extrinsic to the cell. Thus, proteins that regulate the cell cycle are well suited to provide a link between processes that control neuroblast proliferation and differentiation. We reported previously the isolation from brain of a message form of D2 cyclin, one of several cyclin proteins known to promote the progression from G1 to S phase. This MN20/D2 cyclin mRNA is expressed in highly restricted neural populations at embryonic (E) day 15 and postnatal (P) day 6 in the mouse. To gain insight into the role(s) this cyclin may serve in brain formation, the spatial and temporal pattern of MN20/D2 cyclin expression was examined by in situ hybridization at 48 hr intervals from E10.5 to P8. MN20 mRNA was detected in developing cerebellum, dorsal mesencephalon, cerebral cortex, and epithalamus, but not hippocampus, striatum, or thalamus. Comparison with 5-bromodeoxyuridine labeling of cells in S phase indicated that MN20 expression in embryonic cerebellum and cerebral cortex was most pronounced in young neurons that recently had become postmitotic. Although expressed in other embryonic cerebellar neurons, MN20 was detected in granule precursors only postnatally, after their migration from the rhombic lip to the external germinal layer. This indicates that MN20/D2 cyclin is induced in cerebellar granule precursors as they become competent to differentiate. The spatial distribution of MN20 expression in the developing brain suggests that regional differences in cell cycle regulation depend in part on the selective use of cyclin proteins. Moreover, detection of MN20 mRNA in postmitotic neural cells indicates that cyclin D2 expression has effects beyond promoting cell cycle progression and may also have a role in the response of the neural precursor to terminal differentiation signals as the cells exits from proliferation.
尽管在大脑发育过程中增殖与分化的调控长期以来被认为是相互关联的，但协调细胞分裂控制与组织发生的机制仍知之甚少。细胞周期是一个动态过程，受众多细胞周期调节蛋白协同作用的调控，以响应细胞内源性和外源性信号。因此，调节细胞周期的蛋白质非常适合在控制神经母细胞增殖与分化的过程之间提供联系。我们之前报道过从小鼠大脑中分离出一种D2周期蛋白的信使形式，D2周期蛋白是已知的几种促进从G1期进入S期进程的周期蛋白之一。这种MN20/D2周期蛋白mRNA在小鼠胚胎（E）第15天和出生后（P）第6天的高度受限的神经群体中表达。为了深入了解这种周期蛋白在大脑形成中可能发挥的作用，从E10.5到P8每隔48小时通过原位杂交检测MN20/D2周期蛋白表达的时空模式。在发育中的小脑、中脑背侧、大脑皮层和上丘脑检测到MN20 mRNA，但在海马体、纹状体或丘脑中未检测到。与S期细胞的5-溴脱氧尿苷标记进行比较表明，胚胎小脑和大脑皮层中的MN20表达在最近已进入有丝分裂后期的年轻神经元中最为明显。尽管MN20在其他胚胎小脑神经元中也有表达，但仅在颗粒前体细胞从菱唇迁移到外生发层后在出生后才检测到。这表明MN20/D2周期蛋白在小脑颗粒前体细胞具备分化能力时被诱导。MN20在发育中大脑中的表达空间分布表明，细胞周期调控的区域差异部分取决于周期蛋白的选择性使用。此外，在有丝分裂后期神经细胞中检测到MN20 mRNA表明，周期蛋白D2的表达作用不仅限于促进细胞周期进程，在神经前体细胞退出增殖时对终末分化信号的反应中可能也发挥作用。
