Stochastic loss and gain of symmetric divisions in the C. elegans epidermis perturbs robustness of stem cell number.
Stochastic loss and gain of symmetric divisions in the C. elegans epidermis perturbs robustness of stem cell number.
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DOI：
10.1371/journal.pbio.2002429
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发表时间：
2017-11
期刊：
影响因子：
9.8
通讯作者：
Barkoulas M
中科院分区：
文献类型：
--
作者：
Katsanos D;Koneru SL;Mestek Boukhibar L;Gritti N;Ghose R;Appleford PJ;Doitsidou M;Woollard A;van Zon JS;Poole RJ;Barkoulas M
生物系统受制于固有的随机性。然而，发育是非常稳健的，确保了关键表型特征的一致性，例如特定组织中正确的细胞数量。目前尚不清楚哪些基因调节表型变异性，它们与发育基因网络的核心成分有何关系，以及可变表型的发育基础是什么。在这里，我们开始使用秀丽隐杆线虫表皮干细胞（称为缝细胞）的健壮数量作为读数来解决这些问题。我们使用遗传学、细胞谱系追踪和单分子成像来证明lin-22（一种与hes相关的基本螺旋-环-螺旋（bHLH）转录因子）的突变增加了缝细胞数量的可变性。我们发现，表型变异的增加是由于正常对称的细胞分裂在发育过程中随机转化为不对称的，反之亦然，这在相反的方向上影响了终端缝细胞的数量。我们证明LIN-22在表皮基因网络中拮抗Wnt信号通路。然而，lin-22突变体在Wnt通路激活中表现出细胞间的变异性，这与表型变异性相关，并可能驱动表型变异性。我们的研究证明了使用无偏诱变筛选在易感模式生物中研究表型性状变异的可行性。生物体在其经历的每一个分子过程中都暴露于内部和外部的扰动中，而健壮性——维持其系统不变的能力——对它们的发育和生存至关重要。然而，保持细胞可变性尽可能低的过程几乎不为人所知。秀丽隐杆线虫以其高度可复制的发育而著称，在发育过程中表现出几乎不变的细胞分裂和分化模式；因此，它是一种理想的模式生物，在其中寻找基因相同的个体之间调节表型一致性的基因。我们关注的是一组侧表皮细胞-缝细胞-在胚胎后发育过程中经历干细胞样分裂。这些分裂可以是对称的，以增加缝细胞的总数，也可以是不对称的，产生一个子细胞，分化成最终的命运，另一个子细胞保持缝细胞的数量不变。我们在这里表明，转录因子lin-22的突变增加了缝细胞数量的可变性，这是由于对称分裂在发育过程中随机转化为不对称分裂，反之亦然，从而在相反方向上改变了终端缝细胞的数量。我们还表明，观察到的表型变异与保守的Wnt信号通路的随机激活相关。我们的工作表明，发育基因网络的核心组成部分调节多细胞动物的表型变异性。
Biological systems are subject to inherent stochasticity. Nevertheless, development is remarkably robust, ensuring the consistency of key phenotypic traits such as correct cell numbers in a certain tissue. It is currently unclear which genes modulate phenotypic variability, what their relationship is to core components of developmental gene networks, and what is the developmental basis of variable phenotypes. Here, we start addressing these questions using the robust number of Caenorhabditis elegans epidermal stem cells, known as seam cells, as a readout. We employ genetics, cell lineage tracing, and single molecule imaging to show that mutations in lin-22, a Hes-related basic helix-loop-helix (bHLH) transcription factor, increase seam cell number variability. We show that the increase in phenotypic variability is due to stochastic conversion of normally symmetric cell divisions to asymmetric and vice versa during development, which affect the terminal seam cell number in opposing directions. We demonstrate that LIN-22 acts within the epidermal gene network to antagonise the Wnt signalling pathway. However, lin-22 mutants exhibit cell-to-cell variability in Wnt pathway activation, which correlates with and may drive phenotypic variability. Our study demonstrates the feasibility to study phenotypic trait variance in tractable model organisms using unbiased mutagenesis screens. Organisms are exposed to both internal and external perturbations in every molecular process they go through, and robustness—the ability to maintain their systems unchanged—is crucial for their development and survival. However, the processes that keep the variability of cells as low as possible are barely known. The nematode C. elegans is notable for its highly reproducible development, showing an almost invariant pattern of cell division and differentiation during development; it is thus an ideal model organism in which to search for genes that regulate phenotypic consistency among genetically identical individuals. We focus on a group of lateral epidermal cells—the seam cells—which undergo stem cell-like divisions during postembryonic development. These divisions can either be symmetric towards the seam cell fate, acting to increase the total number of cells, or asymmetric, giving rise to one daughter cell that differentiates into its final fate and another one that serves to keep the number of seam cells constant. We show here that mutations in the transcription factor lin-22 increase seam cell number variability due to stochastic conversion of symmetric divisions into asymmetric ones and vice versa during development, thereby altering the number of terminal seam cell number in opposing directions. We also show that the observed phenotypic variability correlates with the stochastic activation of the conserved Wnt signaling pathway. Our work suggests that core components of developmental gene networks modulate phenotypic variability in multicellular animals.
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