Department of Molecular Biophysics & Biochemistry, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, United States of America.
PLoS Genet. 2020 Aug 19;16(8):e1008967. doi: 10.1371/journal.pgen.1008967. eCollection 2020 Aug.
Dysregulation of ribosome production can lead to a number of developmental disorders called ribosomopathies. Despite the ubiquitous requirement for these cellular machines used in protein synthesis, ribosomopathies manifest in a tissue-specific manner, with many affecting the development of the face. Here we reveal yet another connection between craniofacial development and making ribosomes through the protein Paired Box 9 (PAX9). PAX9 functions as an RNA Polymerase II transcription factor to regulate the expression of proteins required for craniofacial and tooth development in humans. We now expand this function of PAX9 by demonstrating that PAX9 acts outside of the cell nucleolus to regulate the levels of proteins critical for building the small subunit of the ribosome. This function of PAX9 is conserved to the organism Xenopus tropicalis, an established model for human ribosomopathies. Depletion of pax9 leads to craniofacial defects due to abnormalities in neural crest development, a result consistent with that found for depletion of other ribosome biogenesis factors. This work highlights an unexpected layer of how the making of ribosomes is regulated in human cells and during embryonic development.
核糖体生成的失调可能导致许多被称为核糖体病的发育障碍。尽管这些用于蛋白质合成的细胞机器在细胞中无处不在，但核糖体病以组织特异性的方式表现出来，其中许多会影响面部的发育。在这里，我们通过蛋白质配对盒 9（PAX9）揭示了颅面发育和核糖体生成之间的另一个联系。PAX9 作为 RNA 聚合酶 II 转录因子发挥作用，调节人类颅面和牙齿发育所需蛋白质的表达。我们现在通过证明 PAX9 在细胞核仁外发挥作用来扩展 PAX9 的这一功能，以调节构建核糖体小亚基所需的蛋白质的水平。PAX9 的这一功能在 Xenopus tropicalis 等生物中是保守的，Xenopus tropicalis 是人类核糖体病的一种既定模型。由于神经嵴发育异常，pax9 的缺失会导致颅面缺陷，这与其他核糖体生物发生因子缺失的结果一致。这项工作强调了核糖体生成在人类细胞和胚胎发育过程中是如何受到调控的。
