Department of Physiology, Development & Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
Nature. 2011 Jul 20;475(7356):381-5. doi: 10.1038/nature10229.
The gene for the atypical NOTCH ligand delta-like homologue 1 (Dlk1) encodes membrane-bound and secreted isoforms that function in several developmental processes in vitro and in vivo. Dlk1, a member of a cluster of imprinted genes, is expressed from the paternally inherited chromosome. Here we show that mice that are deficient in Dlk1 have defects in postnatal neurogenesis in the subventricular zone: a developmental continuum that results in depletion of mature neurons in the olfactory bulb. We show that DLK1 is secreted by niche astrocytes, whereas its membrane-bound isoform is present in neural stem cells (NSCs) and is required for the inductive effect of secreted DLK1 on self-renewal. Notably, we find that there is a requirement for Dlk1 to be expressed from both maternally and paternally inherited chromosomes. Selective absence of Dlk1 imprinting in both NSCs and niche astrocytes is associated with postnatal acquisition of DNA methylation at the germ-line-derived imprinting control region. The results emphasize molecular relationships between NSCs and the niche astrocyte cells of the microenvironment, identifying a signalling system encoded by a single gene that functions coordinately in both cell types. The modulation of genomic imprinting in a stem-cell environment adds a new level of epigenetic regulation to the establishment and maintenance of the niche, raising wider questions about the adaptability, function and evolution of imprinting in specific developmental contexts.
基因非典型的 NOTCH 配体 delta 样同源物 1（Dlk1）编码膜结合和分泌型异构体，在体外和体内的几个发育过程中发挥作用。Dlk1 是一组印迹基因的成员，从父系染色体上表达。在这里，我们表明 Dlk1 缺失的小鼠在脑室下区的出生后神经发生中存在缺陷：这是一个发育连续体，导致嗅球中成熟神经元耗竭。我们表明，DLK1 由龛状星形胶质细胞分泌，而其膜结合型异构体存在于神经干细胞（NSCs）中，并且是分泌的 DLK1 对自我更新的诱导作用所必需的。值得注意的是，我们发现需要从母系和父系染色体上表达 Dlk1。在 NSCs 和龛状星形胶质细胞中选择性地缺失 Dlk1 印记与种系衍生的印迹控制区获得 DNA 甲基化有关。这些结果强调了 NSCs 和微环境中龛状星形胶质细胞之间的分子关系，确定了一个由单个基因编码的信号系统，在两种细胞类型中协调发挥作用。在干细胞环境中调节基因组印迹为龛的建立和维持增加了一个新的表观遗传调控水平，提出了关于印迹在特定发育背景下的适应性、功能和进化的更广泛问题。
