As the major receptor mediated BMP signaling in craniofacial development, Bmpr1a expression 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, Noggin was over-expressed by Osr2-cre^KI to 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 by Noggin over-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 of Bmpr1a in 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 the Noggin over-expression nor Bmpr1a activation 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.

作为颅面发育中主要受体介导的 BMP 信号传导，在E13.5 的前腭架和 E14.5 的后腭架中检测到Bmpr1a表达。然而，使间充质中的 BMP 受体失活只会导致前腭裂或粘膜下腭裂。BMP 信号在后腭间充质和腭成骨中的作用仍然未知。在这项研究中，分泌型 BMP 拮抗剂Noggin被Osr2-cre ^KI过表达强烈抑制小鼠腭间充质中的 BMP 信号传导，这使得新生小鼠表现出完整的腭裂，这种表型比前腭或粘膜下腭裂严重得多。免疫组织化学分析表明，在前、后腭间充质中，经典 BMP-Smad4 信号通路显着下调，而非经典 BMP 信号通路几乎没有改变。尽管仅在前腭间充质中细胞增殖减少，但Noggin在后腭间充质中显着抑制了成骨浓缩和 Osterix 分布过度表达。这些发现表明 BMP-Smad4 信号传导对于前腭间充质中的细胞增殖和后腭间充质中的成骨至关重要。有趣的是，腭间充质中Bmpr1a的组成型激活也导致完全性腭裂，其中增强的 BMP-Smad4 信号导致腭间充质过早成骨分化。此外，无论是Noggin过表达还是Bmpr1a激活破坏了腭架的升高。我们的研究不仅表明 BMP 信号在前、后腭间充质中发挥不同的作用，而且还表明 BMP-Smad4 信号需要对腭间充质的成骨进行微调。