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Abstract：
In vitro modeling is a powerful approach to investigate the pathomechanisms driving human congenital conditions. Here we use human embryonic stem cells (hESCs) to model Nager and Rodriguez syndromes, two craniofacial conditions characterized by hypoplastic neural crest-derived craniofacial bones, caused by pathogenic variants of SF3B4, a core component of the spliceosome. We observed that siRNA-mediated knockdown of SF3B4 interferes with the production of hESC-derived neural crest cells, as seen by a marked reduction in neural crest gene expression. This phenotype is associated with an increase in neural crest cell apoptosis and premature neuronal differentiation. Altogether these results point at a role of SF3B4 in neural crest cell survival, maintenance, and differentiation. We propose that the dysregulation of these processes may contribute to Nager/Rodriguez syndrome associated craniofacial defects.
摘要：
体外建模是研究驱动人类先天性疾病的病理机制的有力方法。在这里，我们使用人类胚胎干细胞（hESCs）来模拟Nager和Rodriguez综合征，两种颅面疾病的特征是发育不良的神经c衍生的颅面骨，由SF3B4的致病变体引起，SF3B4是剪接体的核心组成部分。我们观察到siRNA介导的SF3B4敲低干扰了hESC衍生的神经c细胞的产生，如神经c基因表达显着减少所见。这种表型与神经c细胞凋亡及其过早神经元分化的增加有关。一起,这些结果表明SF3B4在神经c细胞存活中的作用，维护,和分化为Nager/Rodriguez综合征相关颅面缺损的主要原因，并说明体外人类干细胞模型对理解先天性疾病的益处。
