Noack Watt Kristin E, Achilleos Annita, Neben Cynthia L, Merrill Amy E, Trainor Paul A
Stowers Institute for Medical Research, Kansas City, Missouri, United States of America.
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
PLoS Genet. 2016 Jul 22;12(7):e1006187. doi: 10.1371/journal.pgen.1006187. eCollection 2016 Jul.
Ribosome biogenesis is a global process required for growth and proliferation of all cells, yet perturbation of ribosome biogenesis during human development often leads to tissue-specific defects termed ribosomopathies. Transcription of the ribosomal RNAs (rRNAs) by RNA polymerases (Pol) I and III, is considered a rate limiting step of ribosome biogenesis and mutations in the genes coding for RNA Pol I and III subunits, POLR1C and POLR1D cause Treacher Collins syndrome, a rare congenital craniofacial disorder. Our understanding of the functions of individual RNA polymerase subunits, however, remains poor. We discovered that polr1c and polr1d are dynamically expressed during zebrafish embryonic development, particularly in craniofacial tissues. Consistent with this pattern of activity, polr1c and polr1d homozygous mutant zebrafish exhibit cartilage hypoplasia and cranioskeletal anomalies characteristic of humans with Treacher Collins syndrome. Mechanistically, we discovered that polr1c and polr1d loss-of-function results in deficient ribosome biogenesis, Tp53-dependent neuroepithelial cell death and a deficiency of migrating neural crest cells, which are the primary progenitors of the craniofacial skeleton. More importantly, we show that genetic inhibition of tp53 can suppress neuroepithelial cell death and ameliorate the skeletal anomalies in polr1c and polr1d mutants, providing a potential avenue to prevent the pathogenesis of Treacher Collins syndrome. Our work therefore has uncovered tissue-specific roles for polr1c and polr1d in rRNA transcription, ribosome biogenesis, and neural crest and craniofacial development during embryogenesis. Furthermore, we have established polr1c and polr1d mutant zebrafish as models of Treacher Collins syndrome together with a unifying mechanism underlying its pathogenesis and possible prevention.
核糖体生物合成是所有细胞生长和增殖所必需的一个整体过程，然而在人类发育过程中核糖体生物合成受到干扰时，常常会导致组织特异性缺陷，即所谓的核糖体病。由RNA聚合酶（Pol）I和III转录核糖体RNA（rRNA）被认为是核糖体生物合成的限速步骤，编码RNA Pol I和III亚基的基因POLR1C和POLR1D发生突变会导致一种罕见的先天性颅面疾病——特雷彻·柯林斯综合征。然而，我们对单个RNA聚合酶亚基功能的了解仍然很少。我们发现polr1c和polr1d在斑马鱼胚胎发育过程中动态表达，尤其是在颅面组织中。与这种活性模式一致，polr1c和polr1d纯合突变斑马鱼表现出软骨发育不全和颅骨骼异常，这是患有特雷彻·柯林斯综合征的人类的特征。从机制上讲，我们发现polr1c和polr1d功能丧失会导致核糖体生物合成不足、Tp53依赖的神经上皮细胞死亡以及迁移神经嵴细胞的缺乏，而神经嵴细胞是颅面骨骼的主要祖细胞。更重要的是，我们表明对tp53进行基因抑制可以抑制神经上皮细胞死亡，并改善polr1c和polr1d突变体中的骨骼异常，这为预防特雷彻·柯林斯综合征的发病机制提供了一条潜在途径。因此，我们的研究揭示了polr1c和polr1d在胚胎发育过程中rRNA转录、核糖体生物合成以及神经嵴和颅面发育中的组织特异性作用。此外，我们已经将polr1c和polr1d突变斑马鱼确立为特雷彻·柯林斯综合征的模型，并揭示了其发病机制和可能的预防的统一机制。
