Fuz regulates craniofacial development through tissue specific responses to signaling factors.
Fuz regulates craniofacial development through tissue specific responses to signaling factors.
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DOI：
10.1371/journal.pone.0024608
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Amendt BA
中科院分区：
文献类型：
--
作者：
Zhang Z;Wlodarczyk BJ;Niederreither K;Venugopalan S;Florez S;Finnell RH;Amendt BA
平面细胞极性效应基因Fuz调节纤毛发生，Fuz功能缺失研究揭示了一系列胚胎表型。然而，纤毛缺陷可影响许多信号通路，并且在人类中，纤毛缺陷是几种颅面异常的基础。为了解决这个问题，我们分析了Fuz - / - 小鼠的颅面表型和信号反应。我们证明了Fuz在颅面发育过程中对刺猬（Hh）和Wnt / β - 连环蛋白信号传导的独特调节作用。在胚胎发育过程中，Fuz的表达首先出现在背部组织，随后出现在腹部组织和颅面区域，这与纤毛发育一致。Fuz - / - 小鼠表现出严重的颅面畸形，包括无眼、舌和门齿发育不全、下颌发育不良、腭裂、骨化/骨骼缺陷以及增生畸形的 Meckel软骨。在Fuz缺失小鼠中，Hh信号下调，而经典Wnt信号上调，揭示了这两种通路的拮抗关系。由于与Wnt经典靶基因上调和非经典通路基因下调相关的细胞增殖增加，Meckel软骨在Fuz - / - 小鼠中扩张。有趣的是，Fuz缺失小鼠下颌间充质中的纤毛发育减少，这表明纤毛可能在该组织中拮抗Wnt信号。此外，Fuz的表达降低了Wnt通路基因以及一种Wnt依赖性报告基因的表达。最后，染色质免疫沉淀实验表明β - 连环蛋白/ TCF结合直接调节Fuz的表达。这些数据展示了一种Hh和Wnt信号协调的新模型，并揭示了一个依赖Fuz的负反馈回路控制Wnt / β - 连环蛋白信号。
The planar cell polarity effector gene Fuz regulates ciliogenesis and Fuz loss of function studies reveal an array of embryonic phenotypes. However, cilia defects can affect many signaling pathways and, in humans, cilia defects underlie several craniofacial anomalies. To address this, we analyzed the craniofacial phenotype and signaling responses of the Fuz−/− mice. We demonstrate a unique role for Fuz in regulating both Hedgehog (Hh) and Wnt/β-catenin signaling during craniofacial development. Fuz expression first appears in the dorsal tissues and later in ventral tissues and craniofacial regions during embryonic development coincident with cilia development. The Fuz−/− mice exhibit severe craniofacial deformities including anophthalmia, agenesis of the tongue and incisors, a hypoplastic mandible, cleft palate, ossification/skeletal defects and hyperplastic malformed Meckel's cartilage. Hh signaling is down-regulated in the Fuz null mice, while canonical Wnt signaling is up-regulated revealing the antagonistic relationship of these two pathways. Meckel's cartilage is expanded in the Fuz−/− mice due to increased cell proliferation associated with the up-regulation of Wnt canonical target genes and decreased non-canonical pathway genes. Interestingly, cilia development was decreased in the mandible mesenchyme of Fuz null mice, suggesting that cilia may antagonize Wnt signaling in this tissue. Furthermore, expression of Fuz decreased expression of Wnt pathway genes as well as a Wnt-dependent reporter. Finally, chromatin IP experiments demonstrate that β-catenin/TCF-binding directly regulates Fuz expression. These data demonstrate a new model for coordination of Hh and Wnt signaling and reveal a Fuz-dependent negative feedback loop controlling Wnt/β-catenin signaling.
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影响因子：
3
作者：
CHEN, LS;COUWENHOVEN, RI;SNEAD, ML
通讯作者：
SNEAD, ML
DOI：
10.1002/ajmg.c.30231
发表时间：
2009-11-15
影响因子：
3.1
作者：
Baker, Kate;Beales, Philip L.
通讯作者：
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影响因子：
30.8
作者：
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通讯作者：
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DOI：
10.1073/pnas.111092198
发表时间：
2001-06-05
影响因子：
11.1
作者：
Bi, WM;Huang, WD;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
影响因子：
3.5
作者：
Brugmann, Samantha A.;Allen, Nancy C.;Helms, Jill A.
通讯作者：
Helms, Jill A.