Planar cell polarity-mediated induction of neural stem cell expansion during axolotl spinal cord regeneration.
Planar cell polarity-mediated induction of neural stem cell expansion during axolotl spinal cord regeneration.
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DOI：
10.7554/elife.10230
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发表时间：
2015-11-14
期刊：
影响因子：
7.7
通讯作者：
Tanaka EM
中科院分区：
文献类型：
--
作者：
Rodrigo Albors A;Tazaki A;Rost F;Nowoshilow S;Chara O;Tanaka EM
蝾螈是唯一能够动员神经干细胞再生脊髓的所有缺失区域。神经干细胞在损伤后如何在稳态下转化为高度再生的细胞仍然是未知的。在这里，我们表明，在再生过程中，蝾螈神经干细胞抑制神经基因，并重新激活类似于胚胎神经上皮细胞的转录程序。这种去分化包括快速细胞周期的获得、从神经源性分裂到增殖性分裂的转换以及平面细胞极性（PCP）途径组分的重新表达。我们表明，PCP诱导是必不可少的重新定向有丝分裂纺锤体沿着前后轴的伸长，和正交的细胞顶基轴。破坏这种特性会导致过早的神经发生和停止再生。我们的研究结果揭示了PCP在协调脊髓生长的形态发生与从稳态到再生干细胞的转换中的关键作用，再生干细胞可以恢复缺失的组织。DOI：www.example.com成人组织中发现的干细胞对组织修复和维护至关重要。这些细胞以两种主要方式分裂：均等地产生两种新的干细胞，或者不均等地产生一种干细胞和一种可以发育成组织中的一种细胞类型的细胞。生物学家面临的一个关键挑战是了解这些组织驻留干细胞是如何被激活和组织起来再生受伤或缺失的组织的。在蝾螈的整个生命过程中，脊髓中的神经干细胞偶尔会分裂，为健康的脊髓添加新的神经细胞。然而，蝾螈也可以再生部分脊髓，例如如果它的尾巴丢失。在这些条件下，神经干细胞可以转化为高度再生的干细胞，可以产生脊髓再生所需的所有不同类型的细胞。当干细胞成为一种新的细胞类型时，它会激活不同的基因组。因此，Rodrigo Albors，Tazaki等人测量了参与蝾螈脊髓再生的神经干细胞中的基因活性，以揭示这些细胞如何发育成更具再生性的形式。这表明，当美西蝾螈的尾巴被切断时，常驻干细胞会关闭在神经元生成细胞中特别活跃的基因。此外，它们激活了一组类似于形成发育中的神经系统的胚胎细胞中所见的基因。这些基因加速细胞分裂并激活重要的信号通路。该途径-Wnt/PCP途径-履行各种发育作用，其中之一是定向细胞分裂，特别是在伸长组织中。在蝾螈中，这一途径导致干细胞平均分裂以增加可用干细胞的数量，并定向这些分裂的方向以确保再生的脊髓正确伸长。如果这条通路被破坏，细胞就会恢复不均匀分裂，过早地产生神经细胞并停止脊髓的生长。这些发现可以帮助开发修复其他动物受损神经组织的方法，这些动物不能像蝾螈那样再生。DOI：www.example.com网站
Axolotls are uniquely able to mobilize neural stem cells to regenerate all missing regions of the spinal cord. How a neural stem cell under homeostasis converts after injury to a highly regenerative cell remains unknown. Here, we show that during regeneration, axolotl neural stem cells repress neurogenic genes and reactivate a transcriptional program similar to embryonic neuroepithelial cells. This dedifferentiation includes the acquisition of rapid cell cycles, the switch from neurogenic to proliferative divisions, and the re-expression of planar cell polarity (PCP) pathway components. We show that PCP induction is essential to reorient mitotic spindles along the anterior-posterior axis of elongation, and orthogonal to the cell apical-basal axis. Disruption of this property results in premature neurogenesis and halts regeneration. Our findings reveal a key role for PCP in coordinating the morphogenesis of spinal cord outgrowth with the switch from a homeostatic to a regenerative stem cell that restores missing tissue. DOI: http://dx.doi.org/10.7554/eLife.10230.001 Stem cells found in adult tissues are vitally important for tissue repair and maintenance. These cells divide in two main ways: equally to create two new stem cells, or unequally to create a stem cell and a cell that can develop into one of the cell types in the tissue. A key challenge for biologists is to understand how these tissue-resident stem cells are activated and organized to regenerate injured or missing tissue. Throughout the life of the axolotl salamander, neural stem cells in the spinal cord occasionally divide to add new nerve cells to the healthy spinal cord. However, the axolotl can also regenerate part of its spinal cord, for example if its tail is lost. Under these conditions, the neural stem cells can convert into a highly regenerative stem cell that can produce all the different cell types needed to regrow the spinal cord. As a stem cell becomes a new cell type, it activates different sets of genes. Therefore, Rodrigo Albors, Tazaki et al. measured gene activity in the neural stem cells involved in axolotl spinal cord regeneration to uncover how these cells develop into a more regenerative form. This revealed that when an axolotl tail is amputated, resident stem cells turn off the genes that are specifically active in neuron-generating cells. In addition, they activate a similar set of genes to that seen in the embryonic cells that form the developing nervous system. These genes speed up cell division and activate an important signaling pathway. This pathway – the Wnt/PCP pathway – fulfils various developmental roles, one being to orient cell divisions, particularly in elongating tissues. In axolotls, this pathway causes the stem cells to divide equally to increase the number of available stem cells, and orients the direction of these divisions to ensure that the regenerating spinal cord elongates correctly. If this pathway is disrupted, the cells return to dividing unequally, generating nerve cells prematurely and halting the growth of the spinal cord. Such insights could help develop methods of repairing damaged nervous tissue in other animals that cannot regenerate to the extent that axolotls can. DOI: http://dx.doi.org/10.7554/eLife.10230.002