Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function
Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function
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DOI：
10.1038/nm1725
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发表时间：
2008-02-01
期刊：
影响因子：
82.9
通讯作者：
Trainor, Paul A.
中科院分区：
文献类型：
--
作者：
Jones, Natalie C.;Lynn, Megan L.;Trainor, Paul A.
Treacher Collins综合征(TCS)是一种先天性颅面发育障碍，由编码核仁磷蛋白糖浆的TCOF1基因突变引起。TCOF1单倍体缺失扰乱了成熟核糖体的生物发生，导致P53的稳定和Cyclin G1介导的细胞周期停滞，这是TCS特有的神经上皮细胞凋亡和神经脊细胞发育不良的特征。在这里，我们表明，抑制P53可以阻止细胞周期蛋白G1驱动的神经脊细胞的凋亡消除，同时挽救与TCOF1突变相关的颅面畸形，延长寿命。然而，这些改善独立于对核糖体生物发生的影响；因此，表明依赖于P53的神经上皮细胞凋亡是TCS发病的主要机制。我们的工作进一步表明，神经上皮细胞和神经脊细胞在胚胎发生过程中对细胞应激特别敏感，抑制P53功能为临床预防TCS颅面出生缺陷和其他神经营养不良疾病提供了一个有吸引力的途径。
Treacher Collins syndrome (TCS) is a congenital disorder of craniofacial development arising from mutations in TCOF1, which encodes the nucleolar phosphoprotein Treacle. Haploinsufficiency of Tcof1 perturbs mature ribosome biogenesis, resulting in stabilization of p53 and the cyclin G1-mediated cell-cycle arrest that underpins the specificity of neuroepithelial apoptosis and neural crest cell hypoplasia characteristic of TCS. Here we show that inhibition of p53 prevents cyclin G1-driven apoptotic elimination of neural crest cells while rescuing the craniofacial abnormalities associated with mutations in Tcof1 and extending life span. These improvements, however, occur independently of the effects on ribosome biogenesis; thus suggesting that it is p53-dependent neuroepithelial apoptosis that is the primary mechanism underlying the pathogenesis of TCS. Our work further implies that neuroepithelial and neural crest cells are particularly sensitive to cellular stress during embryogenesis and that suppression of p53 function provides an attractive avenue for possible clinical prevention of TCS craniofacial birth defects and possibly those of other neurocristopathies.