Rdh10 loss-of-function and perturbed retinoid signaling underlies the etiology of choanal atresia.
Rdh10 loss-of-function and perturbed retinoid signaling underlies the etiology of choanal atresia.
复制标题
DOI：
10.1093/hmg/ddx031
复制
发表时间：
2017-04-01
影响因子：
3.5
通讯作者：
Trainor PA
中科院分区：
文献类型：
--
作者：
Kurosaka H;Wang Q;Sandell L;Yamashiro T;Trainor PA
颅面的发育是一个复杂的过程，涉及到面部连续性的生长和融合。当这些过程失败时，可能会发生先天性颅面畸形。例如，后鼻孔闭锁（CA）是一种先天性颅面畸形，其中鼻气道和鼻咽之间的连接完全阻塞。CA的发生率约为1/5000，是CHARGE、Treacher柯林斯、Crouzon和Pfeiffer综合征等先天性疾病的常见组成部分。然而，详细的细胞和分子机制支持的病因和发病机制CA仍然难以捉摸。在这项研究中，我们发现，在视黄醇脱氢酶10（Rdh 10），扰乱维生素A代谢和类维生素A信号突变的小鼠，表现出完全渗透CA。有趣的是，我们证明Rdh 10是专门需要在非神经嵴细胞E10.5前适当choorphin的形成，并在Rdh 10的情况下，Fgf 8异位表达在鼻鳍。此外，我们发现，在choorphism发展的缺陷与细胞增殖减少和细胞死亡增加的上皮细胞的发展中的鼻腔，这阻碍了鼻腔的内陷，因此似乎有助于CA的发病机制。综上所述，我们的研究结果表明，RDH 10是必不可少的面部形态发生的早期阶段的功能性鼻气道的形成，并进一步建立RDH 10突变小鼠作为一个重要的模型系统，以研究CA。
Craniofacial development is a complex process that involves sequential growth and fusion of the facial prominences. When these processes fail, congenital craniofacial anomalies can occur. For example, choanal atresia (CA) is a congenital craniofacial anomaly in which the connection between the nasal airway and nasopharynx is completely blocked. CA occurs in approximately 1/5000 live births and is a frequent component of congenital disorders such as CHARGE, Treacher Collins, Crouzon and Pfeiffer syndromes. However, the detailed cellular and molecular mechanisms underpinning the etiology and pathogenesis of CA remain elusive. In this study, we discovered that mice with mutations in retinol dehydrogenase 10 (Rdh10), which perturbs Vitamin A metabolism and retinoid signaling, exhibit fully penetrant CA. Interestingly, we demonstrate Rdh10 is specifically required in non-neural crest cells prior to E10.5 for proper choanae formation, and that in the absence of Rdh10, Fgf8 is ectopically expressed in the nasal fin. Furthermore, we found that defects in choanae development are associated with decreased cell proliferation and increased cell death in the epithelium of the developing nasal cavity, which retards invagination of the nasal cavity, and thus appears to contribute to the pathogenesis of CA. Taken together, our findings demonstrate that RDH10 is essential during the early stages of facial morphogenesis for the formation of a functional nasal airway, and furthermore establish Rdh10 mutant mice as an important model system to study CA.