Institute of Physiological Chemistry and Pathobiochemistry and Cells-in-Motion (CiM) Cluster of Excellence, University of Münster, 48149 Münster, Germany, and
Institutes of, Biophysics, and.
J Neurosci. 2018 Apr 18;38(16):3880-3889. doi: 10.1523/JNEUROSCI.3064-17.2018. Epub 2018 Mar 12.
Fractones are extracellular matrix structures in the neural stem cell niche of the subventricular zone (SVZ), where they appear as round deposits named bulbs or thin branching lines called stems. Their cellular origin and what determines their localization at this site is poorly studied, and it remains unclear whether they influence neural stem and progenitor cell formation, proliferation, and/or maintenance. To address these questions, we analyzed whole-mount preparations of the lateral ventricle of male and female mice by confocal microscopy using different extracellular matrix and cell markers. We found that bulbs are rarely connected to stems and that they contain laminin α5 and α2 chains, respectively. Fractone bulbs were profusely distributed throughout the SVZ and appeared associated with the center of pinwheels, a critical site for adult neurogenesis. We demonstrate that bulbs appear at the apical membrane of ependymal cells at the end of the first week after birth. The use of transgenic mice lacking laminin α5 gene expression () in endothelium and in FoxJ1-expressing ependymal cells revealed ependymal cells as the source of laminin α5-containing fractone bulbs. Deletion of laminin α5 from ependymal cells correlated with a 60% increase in cell proliferation, as determined by phospho-histone H3 staining, and with a selective reduction in the number of slow-dividing cells. These results indicate that fractones are a key component of the SVZ and suggest that laminin α5 modulates the physiology of the neural stem cell niche. Our work unveils key aspects of fractones, extracellular matrix structures that are present in the SVZ that still lack a comprehensive characterization. We show that fractones extensively interact with neural stem cells, whereas some of them are located precisely at pinwheel centers, which are hotspots for adult neurogenesis. Our results also demonstrate that fractones increase in size during aging and that their interactions with neural stem and progenitor cells become more complex in old mice. Last, we show that fractone bulbs are produced by ependymal cells and that their laminin content regulates neural stem cells.
fractones 是脑室下区 (SVZ) 神经干细胞龛中的细胞外基质结构，它们以称为灯泡的圆形沉积物或称为茎的薄分支线的形式出现。它们的细胞起源以及决定它们在该部位定位的因素研究甚少，目前尚不清楚它们是否会影响神经干细胞和祖细胞的形成、增殖和/或维持。为了解决这些问题，我们使用不同的细胞外基质和细胞标记物通过共聚焦显微镜分析了雄性和雌性小鼠侧脑室的全培养物。我们发现灯泡很少与茎相连，并且它们分别包含层粘连蛋白 α5 和 α2 链。 fractone 灯泡在 SVZ 中广泛分布，并出现在与成年神经发生的关键部位风车中心相关的位置。我们证明，灯泡出现在出生后第一周结束时室管膜细胞的顶膜上。使用缺乏内皮细胞中层粘连蛋白 α5 基因表达 () 和 FoxJ1 表达的室管膜细胞的转基因小鼠表明，室管膜细胞是含有层粘连蛋白 α5 的 fractone 灯泡的来源。从室管膜细胞中删除层粘连蛋白 α5 与磷酸组蛋白 H3 染色确定的细胞增殖增加 60%相关，并且与慢分裂细胞数量的选择性减少相关。这些结果表明 fractones 是 SVZ 的关键组成部分，并表明层粘连蛋白 α5 调节神经干细胞龛的生理学。我们的工作揭示了 fractones 的关键方面，这是一种存在于 SVZ 中的细胞外基质结构，仍然缺乏全面的表征。我们表明 fractones 与神经干细胞广泛相互作用，而其中一些位于风车中心的精确位置，这是成年神经发生的热点。我们的结果还表明， fractones 在衰老过程中会增大，并且它们与神经干细胞和祖细胞的相互作用在老年小鼠中变得更加复杂。最后，我们表明 fractone 灯泡是由室管膜细胞产生的，并且它们的层粘连蛋白含量调节神经干细胞。
