Gpr177-mediated Wnt Signaling Is Required for Secondary Palate Development
Gpr177-mediated Wnt Signaling Is Required for Secondary Palate Development
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Gpr177 介导的 Wnt 信号传导是二级上腭发育所必需的
DOI：
10.1177/0022034515583532
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发表时间：
2015-07-01
影响因子：
7.6
通讯作者：
Zhang, Z.
中科院分区：
文献类型：
--
作者：
Liu, Y.;Wang, M.;Zhang, Z.
腭裂是人类主要的先天性出生缺陷之一。尽管外胚层经典Wnt和间充质Wnt信号在腭的次生发育中起着重要作用，但间充质经典Wnt活性在腭次生发育中的功能仍然是难以捉摸的。在这里，我们表明，Gpr 177，一个高度保守的跨膜蛋白必需的Wnt运输，是必需的次生腭发展。gpr 177在小鼠发育过程中腭突上皮和间充质中均有表达。Wnt 1Cre介导的颅面神经嵴细胞中Gpr 177的缺失导致完全性腭裂继发腭裂，其形成主要是由于腭架中细胞异常增殖和细胞死亡增加。通过BATGAL染色，我们揭示了E12.5野生型胚胎的前腭间充质中强烈的典型Wnt活性，但在Gpr 177 Wnt 1-Cre胚胎中没有，这表明Gpr 177介导的间充质Wnt激活的间充质典型Wnt信号传导对次级腭发育至关重要。此外，JNK和c-Jun的磷酸化在Gpr 177 Wnt 1-Cre腭部受损，并通过在体外腭部外植体中植入Wnt 5a浸泡的珠粒来恢复，这表明Gpr 177可能通过Wnt 5a介导的非经典Wnt途径调节腭部发育，其中c-Jun和JNK参与其中。重要的是，缺乏Gpr 177的腭中的某些细胞过程和改变的基因表达与Wnt 5a突变体不同，进一步证明了其他间充质Wnt参与腭发育过程。总之，这些结果表明，间充质Gpr 177是需要通过调节和整合间充质经典和非经典Wnt信号的次生腭发育。
Cleft palate represents one of the major congenital birth defects in humans. Despite the essential roles of ectodermal canonical Wnt and mesenchymal Wnt signaling in the secondary palate development, the function of mesenchymal canonical Wnt activity in secondary palate development remains elusive. Here we show that Gpr177, a highly conserved transmembrane protein essential for Wnt trafficking, is required for secondary palate development. Gpr177 is expressed in both epithelium and mesenchyme of palatal shelves during mouse development. Wnt1Cre-mediated deletion of Gpr177 in craniofacial neural crest cells leads to a complete cleft secondary palate, which is formed mainly due to aberrant cell proliferation and increased cell death in palatal shelves. By BATGAL staining, we reveal an intense canonical Wnt activity in the anterior palate mesenchyme of E12.5 wild-type embryos but not in Gpr177Wnt1-Cre embryos, suggesting that mesenchymal canonical Wnt signaling activated by Gpr177-mediated mesenchymal Wnts is critical for secondary palate development. Moreover, phosphorylation of JNK and c-Jun is impaired in the Gpr177Wnt1-Cre palate and is restored by implantation of Wnt5a-soaked beads in the in vitro palate explants, suggesting that Gpr177 probably regulates palate development via the Wnt5a-mediated noncanonical Wnt pathway in which c-Jun and JNK are involved. Importantly, certain cellular processes and the altered gene expression in palates lacking Gpr177 are distinct from that of the Wnt5a mutant, further demonstrating involvement of other mesenchymal Wnts in the process of palate development. Together, these results suggest that mesenchymal Gpr177 is required for secondary palate development by regulating and integrating mesenchymal canonical and noncanonical Wnt signals.