Indian hedgehog in craniofacial neural crest cells links to skeletal malocclusion by regulating associated cartilage formation and gene expression
Indian hedgehog in craniofacial neural crest cells links to skeletal malocclusion by regulating associated cartilage formation and gene expression
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DOI：
10.1096/fj.201903269r
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发表时间：
2020-03-29
期刊：
影响因子：
4.8
通讯作者：
Kogo, Mikihiko
中科院分区：
文献类型：
--
作者：
Amano, Katsuhiko;Okuzaki, Daisuke;Kogo, Mikihiko
来自神经嵴细胞的额叶颅面骨骼对于面部结构和咀嚼功能至关重要。印度刺猬 (Ihh) 在面部和咀嚼发育中的确切作用尚未得到充分探索。在这项研究中，我们生成了颅面神经嵴细胞特异性 Ihh 缺失小鼠 (Wnt1-Cre;Ihh(fl/fl);Tomato(fl/+))，并发现逐渐侏儒症，但没有围产期致死率。形态学和组织学分析揭示了突变体中明确的颅面表型，我们观察到骨骼错牙合伴随着明显发育不全的鼻上颌复合体和反向切牙咬合。鼻甲骨替代鼻甲软骨和鼻中隔筛骨软骨内骨化均显着延迟。我们还在突变体中观察到下颌骨发育不良，其中下颌支受影响最大。髁突和下颌角软骨均扭曲。然而，牙科检查显示牙齿和牙列没有明显变化。最后，利用髁软骨进行全面的 RNA 序列分析，确定了 Ihh 相关基因网络，包括几个细胞周期基因和 16 个与细胞外基质、硫酸盐转运蛋白、转录因子、受体、纤毛发生因子和粘附分子相关的基因。我们的数据提供了直接的体内证据，表明 Ihh 可能通过激活关键基因在中面部和咀嚼系统形成中发挥着至关重要的作用。
The frontal craniofacial skeleton derived from neural crest cells is vital for facial structure and masticatory functions. The exact role of Indian hedgehog (Ihh) in facial and masticatory development has not been fully explored. In this study, we generated craniofacial neural crest cells-specific Ihh deletion mice (Wnt1-Cre;Ihh(fl/fl);Tomato(fl/+)) and found the gradual dwarfism without perinatal lethality. Morphological and histological analyses revealed unambiguous craniofacial phenotypes in mutants, where we observed skeletal malocclusion accompanied by markedly hypoplastic nasomaxillary complex and reversed incisor occlusion. Both the replacement of nasal concha cartilage by turbinate bones and the endochondral ossification of nasal septum ethmoid bone were substantially delayed. We also observed hypoplastic mandibles in mutants where the mandibular ramus was unexpectedly the most affected. Both the condylar process and mandibular angle cartilages were distorted. However, dental examination showed no significant changes in teeth and dentition. Finally, a comprehensive RNA sequence analysis utilizing condylar cartilage identified Ihh-associated gene network including several cell cycle genes and 16 genes related to the extracellular matrix, sulfate transporters, transcription factors, receptors, a ciliogenesis factor, and an adhesion molecule. Our data provide direct in vivo evidence that Ihh plays crucial roles in midface and masticatory system formation, likely by activating key genes.