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.

生物系统具有固有的随机性。然而，发展非常稳健，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什么关系，以及可变表型的发育基础是什么。在这里，我们开始使用大量的秀丽隐杆线虫表皮干细胞（称为接缝细胞）作为读数来解决这些问题。我们采用遗传学、细胞谱系追踪和单分子成像来显示lin-22中的突变，一个Hes-相关的基本螺旋-环-螺旋（bHLH）转录因子，增加接缝细胞数量的变异性。我们表明，表型变异性的增加是由于在发育过程中正常对称的细胞分裂随机转换为不对称的，反之亦然，这会影响相反方向的末端接缝细胞数量。我们证明 LIN-22 在表皮基因网络中起作用以对抗 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，这与表型变异相关并可能驱动表型变异。我们的研究证明了使用无偏诱变筛选研究易处理模式生物的表型性状变异的可行性。