Coskun Volkan, Luskin Marla B
Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
J Neurosci Res. 2002 Sep 15;69(6):795-802. doi: 10.1002/jnr.10336.
An overriding principle of development is that neurons become permanently postmitotic once they initiate differentiation. Work in our laboratory, however, has provided evidence for a population of progenitor cells in mammalian forebrain that express properties of differentiated neurons, even though they continue to divide. These neuronal progenitor cells are situated in the rostral migratory stream (RMS), which extends from a specialized portion of the subventricular zone surrounding the anterior tip of the lateral ventricle, referred to as the SVZa, to the middle of the olfactory bulb. As SVZa-derived cells migrate to the olfactory bulb, they undergo cell division, and they never deviate from the RMS. Once they reach their final destinations, they become terminally postmitotic interneurons. This Mini-Review concerns findings from our recent experiments designed to reveal the intrinsic and extrinsic mechanisms governing the proliferation and differentiation of the unique SVZa neuronal progenitor cells. We have investigated the role(s) of cell cycle regulatory proteins, in particular, the cell cycle inhibitor p19(INK4d), in the control of SVZa cell proliferation. Several studies have indicated that cells withdraw from the cell cycle once they express p19(INK4d). To begin to investigate whether p19(INK4d)(+) SVZa-derived cells are postmitotic, we analyzed the pattern of p19(INK4d) expression by the cells of the RMS. A pronounced gradient of p19(INK4d) expression was demonstrated; progressively more cells are p19(INK4d) immunoreactive as the olfactory bulb is approached. In addition, the capacity of p19(INK4d)(+) cells to incorporate bromodeoxyuridine was investigated. From the results of these studies, we conclude that SVZa cells in the RMS can successively down-regulate their expression of p19(INK4d) as they migrate and that they repeatedly exit and reenter the cell cycle while en route to the olfactory bulb. These studies led us to investigate whether bone morphogenetic proteins (BMPs) are involved in the regulation of SVZa cell proliferation and p19(INK4d) expression, because, elsewhere in the CNS, BMPs modulate cell proliferation and influence cell fate decisions. To determine the effects of BMP signaling on SVZa cell proliferation and differentiation, we altered the expression of the BMP receptor Ia (BMPR-Ia) using retrovirally mediated gene transfer. The cells in the SVZa encoding the wild-type BMPR-Ia exit the cell cycle and do not appear to migrate through the RMS. Conversely, both within the SVZa and along the RMS, the majority of SVZa-derived cells encoding a dominant-negative BMPR-Ia gene do not express p19(INK4d). These findings indicate that p19(INK4d) expression is suppressed when BMP signaling is inhibited. Furthermore, SVZa-derived cells with both augmented and inhibited BMP signaling retain their neuronal commitment. Collectively, these studies have revealed that SVZa cell proliferation and differentiation is under the control of several interacting intrinsic and extrinsic factors.
发育的一个首要原则是，神经元一旦开始分化就会永久进入有丝分裂后期。然而，我们实验室的研究提供了证据，表明哺乳动物前脑中存在一群祖细胞，它们表现出分化神经元的特性，尽管它们仍在继续分裂。这些神经元祖细胞位于吻侧迁移流（RMS）中，该迁移流从围绕侧脑室前尖端的室下区的一个特殊部分（称为SVZa）延伸至嗅球中部。当源自SVZa的细胞迁移至嗅球时，它们会进行细胞分裂，并且从不偏离RMS。一旦到达最终目的地，它们就会成为终末有丝分裂后期的中间神经元。本综述涉及我们最近的实验结果，这些实验旨在揭示控制独特的SVZa神经元祖细胞增殖和分化的内在和外在机制。我们研究了细胞周期调节蛋白，特别是细胞周期抑制剂p19(INK4d)在控制SVZa细胞增殖中的作用。多项研究表明，细胞一旦表达p19(INK4d)就会退出细胞周期。为了开始研究p19(INK4d)(+)源自SVZa的细胞是否处于有丝分裂后期，我们分析了RMS细胞中p19(INK4d)的表达模式。结果显示p19(INK4d)表达存在明显梯度；随着接近嗅球，p19(INK4d)免疫反应阳性的细胞逐渐增多。此外，我们还研究了p19(INK4d)(+)细胞掺入溴脱氧尿苷的能力。从这些研究结果中，我们得出结论，RMS中的SVZa细胞在迁移过程中可以相继下调其p19(INK4d)的表达，并且它们在前往嗅球的途中会反复退出和重新进入细胞周期。这些研究促使我们研究骨形态发生蛋白（BMPs）是否参与SVZa细胞增殖和p19(INK4d)表达的调节，因为在中枢神经系统的其他部位，BMPs可调节细胞增殖并影响细胞命运决定。为了确定BMP信号对SVZa细胞增殖和分化的影响，我们使用逆转录病毒介导的基因转移改变了BMP受体Ia（BMPR-Ia）的表达。编码野生型BMPR-Ia的SVZa细胞退出细胞周期，似乎不会通过RMS迁移。相反，在SVZa内和沿RMS，大多数编码显性负性BMPR-Ia基因的源自SVZa的细胞不表达p19(INK4d)。这些发现表明，当BMP信号被抑制时，p19(INK4d)的表达会受到抑制。此外，BMP信号增强和抑制的源自SVZa的细胞都保留了它们的神经元定向。总的来说，这些研究表明SVZa细胞的增殖和分化受多种相互作用的内在和外在因素的控制。
