Petersen Petur H, Zou Kaiyong, Hwang Joseph K, Jan Yuh Nung, Zhong Weimin
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06520, USA.
Nature. 2002 Oct 31;419(6910):929-34. doi: 10.1038/nature01124.
Neurons in most regions of the mammalian nervous system are generated over an extended period of time during development. Maintaining sufficient numbers of progenitors over the course of neurogenesis is essential to ensure that neural cells are produced in correct numbers and diverse types. The underlying molecular mechanisms, like those governing stem-cell self-renewal in general, remain poorly understood. We report here that mouse numb and numblike (Nbl), two highly conserved homologues of Drosophila numb, play redundant but critical roles in maintaining neural progenitor cells during embryogenesis, by allowing their progenies to choose progenitor over neuronal fates. In Nbl mutant embryos also conditionally mutant for mouse numb in the nervous system, early neurons emerge in the expected spatial and temporal pattern, but at the expense of progenitor cells, leading to a nearly complete depletion of dividing cells shortly after the onset of neurogenesis. Our findings show that a shared molecular mechanism, with mouse Numb and Nbl as key components, governs the self-renewal of all neural progenitor cells, regardless of their lineage or regional identities.
在发育过程中，哺乳动物神经系统大多数区域的神经元是在一段较长时间内生成的。在神经发生过程中维持足够数量的祖细胞对于确保产生正确数量和多样类型的神经细胞至关重要。其潜在的分子机制，如同一般控制干细胞自我更新的机制一样，仍知之甚少。我们在此报告，小鼠的Numb和Numb样蛋白（Nbl），果蝇Numb的两个高度保守的同源物，在胚胎发育过程中通过使其子代细胞选择祖细胞而非神经元命运，在维持神经祖细胞方面发挥冗余但关键的作用。在神经系统中同时对小鼠Numb进行条件性突变的Nbl突变胚胎中，早期神经元以预期的空间和时间模式出现，但以祖细胞为代价，导致神经发生开始后不久分裂细胞几乎完全耗尽。我们的研究结果表明，以小鼠Numb和Nbl为关键成分的共同分子机制控制着所有神经祖细胞的自我更新，无论其谱系或区域特征如何。
