Department of Molecular Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands ; Department of Medical Microbiology, Academic Medical Center, Amsterdam, The Netherlands.
PLoS One. 2013 Sep 11;8(9):e73997. doi: 10.1371/journal.pone.0073997. eCollection 2013.
Polycomb group (PcG) genes are chromatin modifiers that mediate epigenetic silencing of target genes. PcG-mediated epigenetic silencing is implicated in embryonic development, stem cell plasticity, cell fate maintenance, cellular differentiation and cancer. However, analysis of the roles of PcG proteins in maintaining differentiation programs during vertebrate embryogenesis has been hampered due to the early embryonic lethality of several PcG knock-outs in the mouse. Here, we show that zebrafish Ring1b/Rnf2, the single E3 ubiquitin ligase in the Polycomb Repressive Complex 1, critically regulates the developmental program of craniofacial cell lineages. Zebrafish ring1b mutants display a severe craniofacial phenotype, which includes an almost complete absence of all cranial cartilage, bone and musculature. We show that Cranial Neural Crest (CNC)-derived cartilage precursors migrate correctly into the pharyngeal arches, but fail to differentiate into chondrocytes. This phenotype is specific for cartilage precursors, since other neural crest-derived cell lineages, including glia, neurons and chromatophores, are formed normally in ring1b mutants. Our results therefore reveal a critical and specific role for Ring1b in promoting the differentiation of cranial neural crest cells into chondrocytes. The molecular mechanisms underlying the pathogenesis of craniofacial abnormalities, which are among the most common genetic birth defects in humans, remain poorly understood. The zebrafish ring1b mutant provides a molecular model for investigating these mechanisms and may lead to the discovery of new treatments or preventions of craniofacial abnormalities.
多梳抑制复合物（PcG）基因是一种染色质修饰物，可介导靶基因的表观遗传沉默。PcG 介导的表观遗传沉默与胚胎发育、干细胞可塑性、细胞命运维持、细胞分化和癌症有关。然而，由于几种 PcG 敲除小鼠在早期胚胎中具有致死性，因此分析 PcG 蛋白在维持脊椎动物胚胎发生中分化程序中的作用受到了阻碍。在这里，我们显示斑马鱼 Ring1b/Rnf2，即 Polycomb 抑制复合物 1 中的单个 E3 泛素连接酶，对颅面细胞谱系的发育程序具有关键调节作用。斑马鱼 ring1b 突变体表现出严重的颅面表型，包括几乎完全缺乏所有颅软骨、骨骼和肌肉。我们表明，颅神经嵴（CNC）衍生的软骨前体正确地迁移到咽弓中，但未能分化为软骨细胞。这种表型是软骨前体特有的，因为其他神经嵴衍生的细胞谱系，包括胶质细胞、神经元和色素细胞，在 ring1b 突变体中正常形成。因此，我们的结果揭示了 Ring1b 在促进颅神经嵴细胞分化为软骨细胞中的关键和特异性作用。颅面异常的发病机制，其中包括人类最常见的遗传出生缺陷之一，其分子机制仍知之甚少。斑马鱼 ring1b 突变体为研究这些机制提供了分子模型，并可能导致发现治疗或预防颅面异常的新方法。
