Mandible Development

摘要 SHH基因突变与全前脑综合征、颅面畸形相关 从睫状眼到唇腭裂，再到面中部和下颌发育不良。缺少Shh的小鼠胚胎 表现为单眼，不能形成上下颌骨。胚胎中Shh的组织特异性失活 咽上皮(Shhpeko)或神经脊细胞特异性失活的Smo(Smoncko)，它编码一种 刺猬信号的必需转导，导致小鼠严重的小颌畸形和舌头发育不全。 Shhpeko和Smoncko胚胎均显示神经脊细胞凋亡增加。 胚胎下颌弓，但对介导Shh信号的分子机制知之甚少 下颌骨发育的调控。我们发现Smoncko突变的胚胎在 下颌骨胚胎间充质的口腔侧，导致牙状骨的部分复制。 此外，我们还发现，磷酸化Smad1/5/9和BMP靶基因Msx1、MSX2和ALX4表现出 野生型胚胎下颌弓远端间充质细胞在流产侧的优先表达 在Smoncko突变胚胎中，在下颌弓间充质的口腔侧被异位激活。 由于Bmp4在下颌远端牙弓上皮细胞中表达，而Shh在口腔中表达 上皮细胞在下颌骨发育早期，由于BMP信号已知调节细胞凋亡 和骨形成，这些结果表明了一个关键的，但以前未被认识的机制，涉及 Shh和Bmp4信号通路在发育中口腔-流产轴形成中的相互作用 下颌骨。我们提出了两个全面的具体目标来检验Shh信号调节的假说 Bmp4-Msx1/2和Bmp4-ALX4信号通路在下颌骨发育中的作用 口腔-流产轴上的间充质。这些研究将填补长期存在的对 哺乳动物颌骨口腔-流产轴的分子机制和显著改善我们的 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.