Jagged1 functions downstream of Twist1 in the specification of the coronal suture and the formation of a boundary between osteogenic and non-osteogenic cells.
Jagged1 functions downstream of Twist1 in the specification of the coronal suture and the formation of a boundary between osteogenic and non-osteogenic cells.
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DOI：
10.1016/j.ydbio.2010.08.010
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发表时间：
2010-11-15
影响因子：
2.7
通讯作者：
Maxson RE
中科院分区：
文献类型：
--
作者：
Yen HY;Ting MC;Maxson RE
Notch通路对于包括组织边界形成在内的多种发育过程至关重要。人类JAGGED1杂合性功能缺失可导致以颅缝闭合为特征的Alagille综合征，这一研究表明，JAGGED1可能在颅骨缝线发育中起作用，并参与颅缝闭合的病理生理。我们使用条件基因靶向来检测Jagged1在颅骨穹窿发育中的作用。我们证明Jagged1在中胚层来源的缝合细胞层中表达，这些细胞位于成骨-非成骨边界。我们发现Jagged1在冠状缝的中胚层间室失活，而不是在神经嵴间室失活，导致颅缝闭合。Jagged1的中表皮失活也导致缝合细胞在明显成骨分化之前的身份改变，以及冠状缝线处成骨和非成骨间室边界的缺陷。令人惊讶的是，这些变化与缝合间质中Notch2和Notch效应物Hes1的表达增加有关。它们还与细胞核β-连环蛋白的增加有关。在Twist1突变体中，Jagged1在缝合线中的表达显著减少，表明Twist1和Jagged1之间存在上位性关系。与这种关系相一致的是，Twist1-Jagged1双杂合子的颅缝闭锁严重程度明显高于单个杂合子。因此，我们的研究结果表明，Jagged1是Twist1在冠状缝线发育中的效应因子。
The Notch pathway is crucial for a wide variety of developmental processes including the formation of tissue boundaries. That it may function in calvarial suture development and figure in the pathophysiology of craniosynostosis was suggested by the demonstration that heterozygous loss of function of JAGGED1 in humans can cause Alagille syndrome, which has craniosynostosis as a feature. We used conditional gene targeting to examine the role of Jagged1 in the development of the skull vault. We demonstrate that Jagged1 is expressed in a layer of mesoderm-derived sutural cells that lie along the osteogenic-non-osteogenic boundary. We show that inactivation of Jagged1 in the mesodermal compartment of the coronal suture, but not in the neural crest compartment, results in craniosynostosis. Mesodermal inactivation of Jagged1 also results in changes in the identity of sutural cells prior to overt osteogenic differentiation, as well as defects in the boundary between osteogenic and non-osteogenic compartments at the coronal suture. These changes, surprisingly, are associated with increased expression of Notch2 and the Notch effector, Hes1, in the sutural mesenchyme. They are also associated with an increase in nuclear β-catenin. In Twist1 mutants, Jagged1 expression in the suture is reduced substantially, suggesting an epistatic relationship between Twist1 and Jagged1. Consistent with such a relationship, Twist1-Jagged1 double heterozygotes exhibit a substantial increase in the severity of craniosynostosis over individual heterozygotes. Our results thus suggest that Jagged1 is an effector of Twist1 in coronal suture development.
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