Cranial neural crest ablation of Jagged1 recapitulates the craniofacial phenotype of Alagille syndrome patients
Cranial neural crest ablation of Jagged1 recapitulates the craniofacial phenotype of Alagille syndrome patients
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DOI：
10.1093/hmg/ddr575
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发表时间：
2012-03-15
影响因子：
3.5
通讯作者：
Goudy, Steven
中科院分区：
文献类型：
--
作者：
Humphreys, Ryan;Zheng, Wei;Goudy, Steven
JAGGED1突变导致阿拉杰里综合征，该综合征包含一系列临床症状，包括胆道、心脏和颅面异常。Jagged1是Notch信号通路中的一种配体，在胆道和心脏发育过程中已被广泛研究。然而，JAGGED1在颅面发育过程中的作用却鲜为人知。阿拉杰里综合征患者有面中部发育不全，使其具有特征性的“倒V”形面容。本研究旨在确定Jagged1在颅神经嵴（CNC）细胞中的需求，这些细胞包含颅面发育过程中存在的大部分间充质。此外，通过这种方法，我们以细胞谱系特异性的方式确定了面中部发育过程中Jagged1的自主和非自主需求。利用Wnt1 - cre；Jag1Flox/Flox在CNC中缺失Jagged1重现了阿拉杰里综合征的面中部发育不全表型。Wnt1 - cre；Jag1Flox/Flox小鼠由于下颌错位和咬合不良无法咀嚼，在出生后第30天死亡。Wnt1 - cre；Jag1Flox/Flox小鼠面中部发育不全的病因是面中部细胞增殖减少、血管生成异常（有生产性的血管分支减少）以及通过透明质酸染色显示细胞外基质减少，所有这些都与面中部异常和颅面生长异常有关。利用Wnt1 - cre；Notch1F/F小鼠在CNC中缺失Notch1并没有重现阿拉杰里综合征的面中部发育不全。这些数据表明在发育过程中面中部CNC群体内需要Jagged1，但不需要Notch1。未来的研究将探究Jagged1以细胞自主和细胞非自主方式发挥作用的机制。
JAGGED1 mutations cause Alagille syndrome, comprising a constellation of clinical findings, including biliary, cardiac and craniofacial anomalies. Jagged1, a ligand in the Notch signaling pathway, has been extensively studied during biliary and cardiac development. However, the role of JAGGED1 during craniofacial development is poorly understood. Patients with Alagille syndrome have midface hypoplasia giving them a characteristic oinverted V' facial appearance. This study design determines the requirement of Jagged1 in the cranial neural crest (CNC) cells, which encompass the majority of mesenchyme present during craniofacial development. Furthermore, with this approach, we identify the autonomous and non-autonomous requirement of Jagged1 in a cell lineage-specific approach during midface development. Deleting Jagged1 in the CNC using Wnt1-cre; Jag1 Flox/Flox recapitulated the midfacial hypoplasia phenotype of Alagille syndrome. The Wnt1-cre; Jag1 Flox/Flox mice die at postnatal day 30 due to inability to masticate owing to jaw misalignment and poor occlusion. The etiology of midfacial hypoplasia in the Wnt1-cre; Jag1 Flox/Flox mice was a consequence of reduced cellular proliferation in the midface, aberrant vasculogenesis with decreased productive vessel branching and reduced extracellular matrix by hyaluronic acid staining, all of which are associated with midface anomalies and aberrant craniofacial growth. Deletion of Notch1 from the CNC using Wnt1-cre; Notch1 F/F mice did not recapitulate the midface hypoplasia of Alagille syndrome. These data demonstrate the requirement of Jagged1, but not Notch1, within the midfacial CNC population during development. Future studies will investigate the mechanism in which Jagged1 acts in a cell autonomous and cell non-autonomous manner.