Department of Biology and Biochemistry and Centre for Regenerative Medicine, University of Bath, Bath, United Kingdom.
Department of Human and Molecular Genetics and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America.
PLoS One. 2021 Jan 13;16(1):e0244794. doi: 10.1371/journal.pone.0244794. eCollection 2021.
Understanding how fate specification of distinct cell-types from multipotent progenitors occurs is a fundamental question in embryology. Neural crest stem cells (NCSCs) generate extraordinarily diverse derivatives, including multiple neural, skeletogenic and pigment cell fates. Key transcription factors and extracellular signals specifying NCSC lineages remain to be identified, and we have only a little idea of how and when they function together to control fate. Zebrafish have three neural crest-derived pigment cell types, black melanocytes, light-reflecting iridophores and yellow xanthophores, which offer a powerful model for studying the molecular and cellular mechanisms of fate segregation. Mitfa has been identified as the master regulator of melanocyte fate. Here, we show that an Mitf-related transcription factor, Tfec, functions as master regulator of the iridophore fate. Surprisingly, our phenotypic analysis of tfec mutants demonstrates that Tfec also functions in the initial specification of all three pigment cell-types, although the melanocyte and xanthophore lineages recover later. We show that Mitfa represses tfec expression, revealing a likely mechanism contributing to the decision between melanocyte and iridophore fate. Our data are consistent with the long-standing proposal of a tripotent progenitor restricted to pigment cell fates. Moreover, we investigate activation, maintenance and function of tfec in multipotent NCSCs, demonstrating for the first time its role in the gene regulatory network forming and maintaining early neural crest cells. In summary, we build on our previous work to characterise the gene regulatory network governing iridophore development, establishing Tfec as the master regulator driving iridophore specification from multipotent progenitors, while shedding light on possible cellular mechanisms of progressive fate restriction.
了解多能祖细胞如何特化形成不同的细胞类型是胚胎学的一个基本问题。神经嵴干细胞（NCSCs）能够产生非常多样的衍生物，包括多种神经细胞、骨骼细胞和色素细胞命运。指定 NCSC 谱系的关键转录因子和细胞外信号仍有待确定，而且我们对它们如何以及何时协同作用以控制命运的了解也非常有限。斑马鱼有三种神经嵴衍生的色素细胞类型，即黑色黑色素细胞、反光的虹彩细胞和黄色黄色素细胞，这为研究命运分离的分子和细胞机制提供了强大的模型。Mitfa 已被确定为黑色素细胞命运的主调控因子。在这里，我们表明，一种与 Mitf 相关的转录因子 Tfec 作为虹彩细胞命运的主调控因子发挥作用。令人惊讶的是，我们对 tfec 突变体的表型分析表明，Tfec 也在三种色素细胞类型的最初特化中发挥作用，尽管黑色素细胞和黄色素细胞谱系后来恢复。我们表明，Mitfa 抑制 tfec 的表达，揭示了一种可能的机制，有助于黑色素细胞和虹彩细胞命运之间的决策。我们的数据与长期以来关于局限于色素细胞命运的三潜能祖细胞的提议一致。此外，我们研究了 tfec 在多潜能 NCSCs 中的激活、维持和功能，首次证明了它在形成和维持早期神经嵴细胞的基因调控网络中的作用。总之，我们在之前的工作基础上，对调控虹彩细胞发育的基因调控网络进行了表征，确立了 Tfec 作为从多潜能祖细胞驱动虹彩细胞特化的主调控因子，同时阐明了可能的细胞命运限制的机制。
