Tcof1/Treacle is required for neural crest cell formation and proliferation deficiencies that cause craniofacial abnormalities
Tcof1/Treacle is required for neural crest cell formation and proliferation deficiencies that cause craniofacial abnormalities
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DOI：
10.1073/pnas.0603730103
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发表时间：
2006-09-05
影响因子：
11.1
通讯作者：
Trainor, Paul A.
中科院分区：
文献类型：
--
作者：
Dixon, Jill;Jones, Natalie C.;Trainor, Paul A.
神经嵴细胞是一种迁移性细胞群，其产生头部中的大部分软骨、骨、结缔组织和感觉神经节。神经嵴细胞生命周期的形成、增殖、迁移和分化阶段异常可导致颅面畸形，占所有先天性出生缺陷的三分之一。Treacher柯林斯综合征（TCS）以面骨发育不全、腭裂、中耳和外耳缺损为特征。虽然TCS是由TCOF 1基因的常染色体显性突变引起的，但在这种情况下观察到的异常的机制起源尚不清楚，并且TCOF 1编码的蛋白质Treacle的功能仍然知之甚少。为了研究TCS的发育基础，我们通过Tcof 1的种系突变产生了小鼠模型。Tcof 1的单倍不足导致迁移神经嵴细胞的缺陷，从而导致严重的颅面畸形。我们证明了Tcof 1/Treacle是神经嵴细胞的形成和增殖所需的细胞自主。Tcof 1/Treacle通过控制成熟核糖体的产生来调节增殖。因此，Tcof 1/Treacle是核糖体生物发生的独特时空调节因子，这种缺陷破坏神经嵴细胞的形成和增殖，导致TCS颅面异常的发育不全特征。
Neural crest cells are a migratory cell population that give rise to the majority of the cartilage, bone, connective tissue, and sensory ganglia in the head. Abnormalities in the formation, proliferation, migration, and differentiation phases of the neural crest cell life cycle can lead to craniofacial malformations, which constitute one-third of all congenital birth defects. Treacher Collins syndrome (TCS) is characterized by hypoplasia of the facial bones, cleft palate, and middle and external ear defects. Although TCS results from autosomal dominant mutations of the gene TCOF1, the mechanistic origins of the abnormalities observed in this condition are unknown, and the function of Treacle, the protein encoded by TCOF1, remains poorly understood. To investigate the developmental basis of TCS we generated a mouse model through germ-line mutation of Tcof1. Haploinsufficiency of Tcof1 leads to a deficiency in migrating neural crest cells, which results in severe craniofacial malformations. We demonstrate that Tcof1/Treacle is required cell-autonomously for the formation and proliferation of neural crest cells. Tcof1/Treacle regulates proliferation by controlling the production of mature ribosomes. Therefore, Tcof1/Treacle is a unique spatiotemporal regulator of ribosome biogenesis, a deficiency that disrupts neural crest cell formation and proliferation, causing the hypoplasia characteristic of TCS craniofacial anomalies.