Interaction between Foxc1 and Fgf8 during mammalian jaw patterning and in the pathogenesis of syngnathia.
Interaction between Foxc1 and Fgf8 during mammalian jaw patterning and in the pathogenesis of syngnathia.
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DOI：
10.1371/journal.pgen.1003949
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Trainor PA
中科院分区：
文献类型：
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作者：
Inman KE;Purcell P;Kume T;Trainor PA
Syngnathia（上下颌骨融合）是一种罕见的人类先天性疾病，文献报道的病例不到六十例。合颌畸形通常表现为复杂综合征的一部分，包括广泛的口腔和颌面部异常，但也可以单独发生。头部和面部的大多数软骨、骨骼和结缔组织都源自神经嵴细胞。因此，先天性颅面异常通常归因于神经嵴细胞形成、存活、迁移或分化的缺陷。然而，合颌畸形的病因和发病机制仍不清楚。在这里，我们报告 Foxc1 无效胚胎表现出骨性合颌以及上颌和下颌结构缺陷以及颞下颌关节 (TMJ) 发育不全。在缺乏 Foxc1 的情况下，神经嵴细胞衍生的成骨模式会受到影响，因为成骨细胞在上颌骨突出处异位发育并与牙骨融合。此外，我们观察到 Foxc1 缺失小鼠的颅面肌肉组织也受到干扰，这凸显了正常下颌发育所需的复杂组织相互作用。我们提供的证据表明 Foxc1 和 Fgf8 在遗传上相互作用，并且 Fgf8 剂量与联颌表型的变异相关。我们的数据共同表明，Foxc1 – Fgf8 信号传导调节哺乳动物下颌模式，并为合颌的发病机制提供了机制基础。此外，我们的工作为理解颌部模式和其他先天性颅面异常（包括颞下颌关节发育不全）的病因学提供了一个框架。大约三分之一患有先天缺陷的婴儿会出现头部和面部畸形。异常可能包括唇裂、腭裂以及骨骼和肌肉发育异常。这些缺陷导致婴儿死亡率显着，并对患者造成终生的身体和社会后果。改善修复和制定预防策略需要彻底了解有助于正常颅面发育和疾病发病机制的潜在遗传、分子和环境因素。在这项研究中，我们报告了第一个合颌遗传模型，这是一种罕见的人类颅面缺陷，其特征是上下颌骨融合。我们发现 Foxc1 是颌骨和肌肉以及颌关节正常发育所必需的。我们的研究为理解人类合颌的原因以及颌关节形成失败提供了机制基础。此外，我们的工作增强了我们对颌骨发育的了解，并可能为合颌和相关颅面畸形患者的治疗策略提供参考。
Syngnathia (bony fusion of the upper and lower jaw) is a rare human congenital condition, with fewer than sixty cases reported in the literature. Syngnathia typically presents as part of a complex syndrome comprising widespread oral and maxillofacial anomalies, but it can also occur in isolation. Most cartilage, bone, and connective tissue of the head and face is derived from neural crest cells. Hence, congenital craniofacial anomalies are often attributed to defects in neural crest cell formation, survival, migration, or differentiation. The etiology and pathogenesis of syngnathia however remains unknown. Here, we report that Foxc1 null embryos display bony syngnathia together with defects in maxillary and mandibular structures, and agenesis of the temporomandibular joint (TMJ). In the absence of Foxc1, neural crest cell derived osteogenic patterning is affected, as osteoblasts develop ectopically in the maxillary prominence and fuse with the dentary bone. Furthermore, we observed that the craniofacial musculature is also perturbed in Foxc1 null mice, which highlights the complex tissue interactions required for proper jaw development. We present evidence that Foxc1 and Fgf8 genetically interact and that Fgf8 dosage is associated with variation in the syngnathic phenotype. Together our data demonstrates that Foxc1 – Fgf8 signaling regulates mammalian jaw patterning and provides a mechanistic basis for the pathogenesis of syngnathia. Furthermore, our work provides a framework for understanding jaw patterning and the etiology of other congenital craniofacial anomalies, including temporomandibular joint agenesis. Approximately one-third of all babies born with congenital defects, exhibit malformations of the head and face. Anomalies can include cleft lip, cleft palate, and abnormal development of bones and muscles. Such defects result in significant infant mortality, as well as life-long physical and social consequences for patients. Improved repair and the development of prevention strategies requires a thorough understanding of the underlying genetic, molecular, and environmental factors that contribute to normal craniofacial development and the pathogenesis of disease. In this study, we report the first genetic model of syngnathia, a rare human craniofacial defect characterized by bony fusion of the upper and lower jaw. We discovered that Foxc1 is required for normal development of the bones and muscles of the jaw as well as the jaw joint. Our studies provide a mechanistic basis for understanding the cause of human syngnathia as well as the failure of jaw joint formation. Furthermore, our work enhances our knowledge of jaw development and may inform treatment strategies for patients with syngnathia and related craniofacial malformation conditions.