Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, California 94143, USA.
Nature. 2010 Mar 25;464(7288):554-561. doi: 10.1038/nature08845.
Neurons in the developing rodent cortex are generated from radial glial cells that function as neural stem cells. These epithelial cells line the cerebral ventricles and generate intermediate progenitor cells that migrate into the subventricular zone (SVZ) and proliferate to increase neuronal number. The developing human SVZ has a massively expanded outer region (OSVZ) thought to contribute to cortical size and complexity. However, OSVZ progenitor cell types and their contribution to neurogenesis are not well understood. Here we show that large numbers of radial glia-like cells and intermediate progenitor cells populate the human OSVZ. We find that OSVZ radial glia-like cells have a long basal process but, surprisingly, are non-epithelial as they lack contact with the ventricular surface. Using real-time imaging and clonal analysis, we demonstrate that these cells can undergo proliferative divisions and self-renewing asymmetric divisions to generate neuronal progenitor cells that can proliferate further. We also show that inhibition of Notch signalling in OSVZ progenitor cells induces their neuronal differentiation. The establishment of non-ventricular radial glia-like cells may have been a critical evolutionary advance underlying increased cortical size and complexity in the human brain.
发育中的啮齿动物皮层中的神经元由作为神经干细胞的放射状胶质细胞产生。这些上皮细胞排列在脑室周围,并产生中间祖细胞,这些细胞迁移到脑室下区 (SVZ) 并增殖以增加神经元数量。发育中的人类 SVZ 具有一个大大扩展的外部区域 (OSVZ),被认为有助于皮层的大小和复杂性。然而,OSVZ 祖细胞类型及其对神经发生的贡献尚不清楚。在这里,我们表明大量的放射状胶质样细胞和中间祖细胞存在于人类 OSVZ 中。我们发现 OSVZ 放射状胶质样细胞具有长的基底突起,但令人惊讶的是,它们是非上皮细胞,因为它们与脑室表面没有接触。通过实时成像和克隆分析,我们证明这些细胞可以进行增殖分裂和自我更新的不对称分裂,产生可以进一步增殖的神经元祖细胞。我们还表明,抑制 OSVZ 祖细胞中的 Notch 信号通路会诱导其神经元分化。非脑室放射状胶质样细胞的建立可能是人类大脑皮层大小和复杂性增加的关键进化进展。