Mandible Development

摘要 SHH突变与前脑无裂综合征和颅面畸形有关 从独眼畸形到唇腭裂到面中部和下颌发育不全。缺乏Shh的小鼠胚胎 出现独眼畸形，不能形成上颌骨和下颌骨。胚胎中Shh的组织特异性失活 咽上皮（Shhpeko）或Smo（Smoncko）的神经嵴细胞特异性失活，Smo编码一种 hedgehog信号传导的专性转导子，导致小鼠严重的小颌畸形和舌发育不全。 Shhpeko和Smoncko胚胎的神经嵴细胞凋亡增加， 胚胎下颌弓，但很少有人知道的分子机制介导的Shh信号 下颌骨发育的调节。我们发现，Smoncko突变体胚胎表现出异位骨化， 胚胎下颌间充质的口侧，导致部分齿骨的复制。 此外，我们发现磷酸化Smad 1/5/9和BMP靶基因Msx 1，Msx 2和Alx 4， 在野生型胚胎的远侧下颌弓间充质的背口侧优先表达， 在Smoncko突变胚胎中，在下颌弓间充质的口侧异位激活。 由于Bmp 4在下颌弓远端上皮中表达，而Shh在口腔中表达， 由于已知BMP信号传导调节细胞凋亡， 和骨形成，这些结果表明了一个重要的，但以前未被认识到的机制， Shh和Bmp 4信号通路在发育中的口腔-背口轴模式中的相互作用 下颌骨我们提出了两个全面的具体目标，以测试这一假设，Shh信号调节 Bmp 4-Msx 1/2和Bmp 4-Alx 4通路控制发育中下颌骨的存活和形成 间充质沿着口背轴。这些研究将填补长期以来在理解 分子机制模式的哺乳动物颌骨的口-背口轴，并显着提高我们的 了解下颌骨发育缺陷的发病机制。

Abstract Mutations in SHH are associated with holoprosencephaly syndromes, with craniofacial malformations ranging from cyclopia to cleft lip/palate to midfacial and mandibular hypoplasia. Mouse embryos lacking Shh exhibit cyclopia and fail to form maxilla and mandible. Tissue-specific inactivation of Shh in the embryonic pharyngeal epithelium (Shhpeko) or neural crest cell-specific inactivation of Smo (Smoncko), which encodes an obligatory transducer of hedgehog signaling, results in severe micrognathia and tongue agenesis in mice. Both Shhpeko and Smoncko embryos showed increased apoptosis of neural crest cells populating the embryonic mandibular arches, but little is known about the molecular mechanisms mediating Shh signaling regulation of mandible development. We found that the Smoncko mutant embryos exhibit ectopic ossification in the oral side of the embryonic mandibular mesenchyme, leading to partial duplication of the dentary bones. Furthermore, we found that phospho-Smad1/5/9 and BMP target genes Msx1, Msx2, and Alx4, exhibit preferential expression in the aboral side of the distal mandibular arch mesenchyme in wildtype embryos but are ectopically activated in the oral side of the mandibular arch mesenchyme in Smoncko mutant embryos. Since Bmp4 is expressed in the distal mandibular arch epithelium, whereas Shh is expressed in the oral epithelium during early mandibular development, and since BMP signaling is known to regulate apoptosis and bone formation, these results suggest a crucial, but previously unappreciated, mechanism involving interactions of Shh and Bmp4 signaling pathways in patterning the oral-aboral axis of the developing mandible. We proposed two comprehensive specific aims to test the hypothesis that Shh signaling regulates the Bmp4-Msx1/2 and Bmp4-Alx4 pathways to control survival and patterning of the developing mandibular mesenchyme along the oral-aboral axis. These studies will fill a longstanding gap in the understanding of molecular mechanisms patterning the oral-aboral axis of the mammalian jaw and significantly improve our understanding of pathogenic mechanisms of mandibular developmental defects.