Mandible Development

下颌骨发育

• 批准号: 9363466
• 负责人: RULANG JIANG
• 金额: $ 64.16万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-10 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9363466
• 关键词: Apoptosis; Biological Assay; Breathing; CRISPR/Cas technology; ChIP-seq; Cleft Palate; Congenital Abnormality; Craniofacial Abnormalities; Defect; Deglutition; Development; Distal; Ectopic Expression; Embryo; Epithelium; Etiology; Exhibits; FOXF1 gene; Family; Foxes; Gene Targeting; Genes; Genetic; Heterotopic Ossification; Holoprosencephaly; Human; Jaw; Label; Limb structure; MSX1 gene; Mandible; Maxilla; Mediating; Medical; Mesenchyme; Messenger RNA; Methods; Micrognathism; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Neural Crest Cell; Operative Surgical Procedures; Oral; Osteogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Play; Prevention; Process; Regulation; Regulator Genes; Role; SHH gene; Side; Signal Pathway; Signal Transduction; Syndrome; Testing; Tissues; Tongue; Transducers; bone; cleft lip and palate; clinical care; clinical development; conditional mutant; craniofacial; experience; genome editing; improved; insight; member; mutant; mutant mouse model; oral cavity epithelium; prevent; smoothened signaling pathway; transcription factor; transcriptome sequencing; treatment strategy

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.

抽象的 SHH中的突变与颅面畸形有关，颅面畸形 从环岛到唇裂/pa裂到中腹和下颌骨发育不全的范围。鼠标缺乏SHH 展示环境，无法形成上颌和下颌骨。胚胎中SHH的组织特异性灭活 咽上皮（Shhpeko）或Smo（Smoncko）的神经rest细胞特异性灭活，该灭活（Smoncko）编码 刺猬信号传导的强制性传感器，导致小鼠的严重微处理和舌发性。 Shhpeko和Smoncko胚胎均显示出填充神经crest细胞的凋亡增加 胚胎下颌弓，但对介导SHH信号的分子机制知之甚少 下颌骨发展的规定。我们发现Smoncko突变体胚胎在 胚胎下颌间质的口腔侧，导致牙齿的部分重复。 此外，我们发现Phosho-Smad1/5/9和BMP靶基因MSX1，MSX2和ALX4展示 在野生型胚胎中远端下颌弓间质的焦点的优先表达 在Smoncko突变胚胎中的下颌弓间质的口腔中被异位激活。 由于BMP4在下颌骨拱形上皮中表达 早期下颌发育期间的上皮，并且已知BMP信号传导调节细胞凋亡 这些结果和骨形成，这些结果表明至关重要但以前没有批准的机制，涉及 SHH和BMP4信号通路的相互作用在对发育中的口腔久经轴模式时 下颌骨。我们提出了两个全面的特定目的，以检验SHH信号调节的假设 BMP4-MSX1/2和BMP4-ALX4途径控制发展的下颌生存和模式 沿着口腔焦点轴的间充质。这些研究将填补对理解的长期差距 分子机制，使哺乳动物颌骨的口腔透明轴形成，并显着改善了我们的 了解下颌发育缺陷的致病机制。