Schmetsdorf Stefanie, Gärtner Ulrich, Arendt Thomas
Department of Neuroanatomy, Paul Flechsig Institute for Brain Research, University of Leipzig, Jahnallee 59, 04109 Leipzig, Germany.
Int J Dev Neurosci. 2005 Feb;23(1):101-12. doi: 10.1016/j.ijdevneu.2004.07.019.
Developmental structuring of brain is the result of a strictly coordinated process that involves controlled cell division, neuronal migration and terminal differentiation. Neurogenesis occurs generally during embryonic and early postnatal stages and will be finished in the mature brain. Once differentiated, neurons are incapable of further division but retain the capability of structural and functional plasticity. However, there are distinct regions in the adult brain of mammals that generate neurons continuously throughout life. Among them, the hippocampus, which is known as a region with a high degree of neuroplasticity, is of particular interest in the context of adult neurogenesis. In general, progression through cell cycle phases is regulated by the sequential expression and activation of regulatory proteins like cyclin dependent kinases (cdk), cyclins, or cdk inhibitors (cdki). In postmitotic and terminally differentiated neurons, cell cycle activity is arrested by enrichment of cdkis. The timing of cell cycle exit and neuronal differentiation is likely to be regulated in part by cell cycle regulatory proteins. However, the expression of cell cycle markers in the postnatal or adult brain is still a matter of controversial debate. In the present study, we examined the expression of cdks, cyclins and cdkis within the mouse hippocampus at different developmental stages (embryonic days 17, 19; postnatal day 11 and adult) using immunohistochemical methods. During the prenatal development, cell cycle proteins were localized predominantly in nuclei of all presumptive neuronal populations but expression was not restricted to proliferative cells. With developmental progression, the subcellular localization of most markers was increasingly shifted from nuclear to the cytoplasmic compartment. However, even in the adult, cell cycle-related proteins were found in terminally differentiated pyramidal and granule neurons. Here, they were mainly localized in the perikaryal cytoplasm but only sporadically in neuronal nuclei. Occasionally, immunoreactivity was also found in dendrites and mossy fibers. The present results suggest that cell cycle arrest and terminal differentiation is not necessarily incompatible with the expression of cell cycle-related markers. Thus, they may have supplementary functions in differentiated neurons that might be associated with neuronal plasticity.
大脑的发育结构是一个严格协调过程的结果，该过程涉及受控的细胞分裂、神经元迁移和终末分化。神经发生通常发生在胚胎期和出生后早期阶段，并在成熟大脑中完成。一旦分化，神经元就无法进一步分裂，但保留结构和功能可塑性的能力。然而，在成年哺乳动物大脑中有不同区域终生持续产生神经元。其中，海马体作为一个具有高度神经可塑性的区域，在成体神经发生的背景下特别受关注。一般来说，细胞周期各阶段的进展受细胞周期蛋白依赖性激酶（cdk）、细胞周期蛋白或cdk抑制剂（cdki）等调节蛋白的顺序表达和激活所调控。在有丝分裂后和终末分化的神经元中，细胞周期活性因cdkis的富集而停滞。细胞周期退出和神经元分化的时间可能部分受细胞周期调节蛋白调控。然而，细胞周期标志物在出生后或成年大脑中的表达仍是一个有争议的问题。在本研究中，我们使用免疫组化方法检测了不同发育阶段（胚胎第17天、19天；出生后第11天和成年）小鼠海马体中cdk、细胞周期蛋白和cdki的表达。在产前发育期间，细胞周期蛋白主要定位于所有假定神经元群体的细胞核中，但表达并不局限于增殖细胞。随着发育进程，大多数标志物的亚细胞定位逐渐从细胞核转移到细胞质区室。然而，即使在成年期，在终末分化的锥体神经元和颗粒神经元中也发现了细胞周期相关蛋白。在这里，它们主要定位于胞体细胞质中，但仅偶尔出现在神经元细胞核中。偶尔，在树突和苔藓纤维中也发现了免疫反应性。目前的结果表明，细胞周期停滞和终末分化不一定与细胞周期相关标志物的表达不相容。因此，它们可能在分化神经元中具有补充功能，这可能与神经元可塑性相关。
