Altered BMP-Smad4 signaling causes complete cleft palate by disturbing osteogenesis in palatal mesenchyme
Altered BMP-Smad4 signaling causes complete cleft palate by disturbing osteogenesis in palatal mesenchyme
复制标题
BMP-Smad4 信号改变通过干扰腭间充质中的成骨而导致完全腭裂
DOI：
10.1007/s10735-020-09922-4
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发表时间：
2020-11-07
影响因子：
3.2
通讯作者：
Liu, Chao
中科院分区：
文献类型：
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作者：
Li, Nan;Liu, Jing;Liu, Chao
作为颅面发育中BMP信号传导的主要受体，Bmpr 1a在E13.5的前腭架和E14.5的后腭架中检测到表达。然而，间充质中BMP受体失活仅导致前腭裂或粘膜下腭裂。BMP信号在后腭间充质和腭骨形成中的作用尚不清楚。本研究利用Osr 2-creKI过量表达BMP拮抗剂Noggin，在小鼠腭间充质中强烈抑制BMP信号，使新生小鼠出现完全性腭裂，其表型远比前腭裂或粘膜下腭裂严重。免疫组织化学分析表明，在前，后腭间充质，经典的BMP-Smad 4信号显着下调，而非经典的BMP信号通路的改变很小。虽然细胞增殖仅在前腭间充质中减少，但成骨凝聚和Osterix分布在后腭间充质中被Noggin过度表达显著抑制。这些结果表明，BMP-Smad 4信号是必不可少的前腭间充质细胞增殖，并在后腭间充质成骨。有趣的是，BMP 1在腭间充质中的组成性激活也导致了完全性腭裂，其中增强的BMP-Smad 4信号导致腭间充质中的过早成骨分化。此外，Noggin的过度表达和Bmpr 1a的激活都没有破坏腭架的升高。我们的研究不仅表明BMP信号在前腭和后腭间充质中发挥了不同的作用，而且还表明BMP-Smad 4信号需要微调腭间充质的成骨。
As the major receptor mediated BMP signaling in craniofacial development,Bmpr1aexpression was detected in the anterior palatal shelves from E13.5 and the posterior palatal shelves from E14.5. However, inactivating BMP receptor in the mesenchyme only leads to anterior cleft palate or submucous cleft palate. The role of BMP signaling in posterior palatal mesenchyme and palatal osteogenesis is still unknown. In this study, a secreted BMP antagonist,Nogginwas over-expressed byOsr2-creKIto suppress BMP signaling intensively in mouse palatal mesenchyme, which made the newborn mouse displaying complete cleft palate, a phenotype much severer than the anterior or submucous cleft palate. Immunohistochemical analysis indicated that in the anterior and posterior palatal mesenchyme, the canonical BMP-Smad4 signaling was dramatically down-regulated, while the non-canonical BMP signaling pathways were altered little. Although cell proliferation was reduced only in the anterior palatal mesenchyme, the osteogenic condensation and Osterix distribution were remarkably repressed in the posterior palatal mesenchyme byNogginover-expression. These findings suggested that BMP-Smad4 signaling was essential for the cell proliferation in the anterior palatal mesenchyme, and for the osteogenesis in the posterior palatal mesenchyme. Interestingly, the constitutive activation ofBmpr1ain palatal mesenchyme also caused the complete cleft palate, in which the enhanced BMP-Smad4 signaling resulted in the premature osteogenic differentiation in palatal mesenchyme. Moreover, neither theNogginover-expression norBmpr1aactivation disrupted the elevation of palatal shelves. Our study not only suggested that BMP signaling played the differential roles in the anterior and posterior palatal mesenchyme, but also indicated that BMP-Smad4 signaling was required to be finely tuned for the osteogenesis of palatal mesenchyme.