A signaling cascade involving endothelin-1, dHAND and msx1 regulates development of neural-crest-derived branchial arch mesenchyme.
A signaling cascade involving endothelin-1, dHAND and msx1 regulates development of neural-crest-derived branchial arch mesenchyme.
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发表时间：
1998-08
期刊：
影响因子：
4.6
通讯作者：
Tiffani Thomas;Hiroki Kurihara;Hiroyuki Yamagishi;Y. Kurihara;Yoshio Yazaki;Eric N. Olson;Deepak Srivastava
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文献类型：
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作者：
Tiffani Thomas;Hiroki Kurihara;Hiroyuki Yamagishi;Y. Kurihara;Yoshio Yazaki;Eric N. Olson;Deepak Srivastava
许多人类综合症是颅神经嵴发育异常的结果。一组此类缺陷被称为 CATCH-22（心脏缺陷、相貌异常、胸腺发育不全、腭裂、低钙血症，与 22 号染色体微缺失相关）综合征，表现出由第三和第四神经嵴衍生的鳃弓和鳃弓动脉异常发育引起的颅面和心脏缺陷。内皮素 1 基因 (Edn1) 存在无效突变，该基因表达于鳃弓上皮层，编码内皮素 1 (ET-1) 信号肽，其表型与 CATCH-22 综合征相似，伴有主动脉弓缺陷和颅面异常。在这里，我们发现基本的螺旋-环-螺旋转录因子 dHAND 在鳃弓上皮下的间充质中表达。此外，dHAND 和相关基因 eHAND 在 Edn1 缺失胚胎的鳃弓和主动脉弓中下调。在 dHAND 基因纯合缺失的小鼠中，第一和第二弓由于程序性细胞死亡而发育不全，而第三和第四弓无法形成。分子分析显示，鳃弓神经嵴衍生成分的大多数标记物在 dHAND 缺失胚胎中表达，表明神经嵴细胞的正常迁移。然而，同源框基因 Msx1 的表达在 dHAND 缺失鳃弓的间充质中检测不到，但在肢芽中不受影响，这与之前描述的 Msx1 的可分离调节元件一致。总之，这些数据表明了一个模型，其中 ET-1 的上皮分泌刺激 dHAND 的间充质表达，dHAND 调节生长的远端鳃弓中的 Msx1 表达。该分子途径的完全破坏会导致鳃弓因细胞凋亡而生长失败，而部分破坏会导致鳃弓衍生物的缺陷，类似于 CATCH-22 综合征中所见的情况。
Numerous human syndromes are the result of abnormal cranial neural crest development. One group of such defects, referred to as CATCH-22 (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, hypocalcemia, associated with chromosome 22 microdeletion) syndrome, exhibit craniofacial and cardiac defects resulting from abnormal development of the third and fourth neural crest-derived branchial arches and branchial arch arteries. Mice harboring a null mutation of the endothelin-1 gene (Edn1), which is expressed in the epithelial layer of the branchial arches and encodes for the endothelin-1 (ET-1) signaling peptide, have a phenotype similar to CATCH-22 syndrome with aortic arch defects and craniofacial abnormalities. Here we show that the basic helix-loop-helix transcription factor, dHAND, is expressed in the mesenchyme underlying the branchial arch epithelium. Further, dHAND and the related gene, eHAND, are downregulated in the branchial and aortic arches of Edn1-null embryos. In mice homozygous null for the dHAND gene, the first and second arches are hypoplastic secondary to programmed cell death and the third and fourth arches fail to form. Molecular analysis revealed that most markers of the neural-crest-derived components of the branchial arch are expressed in dHAND-null embryos, suggesting normal migration of neural crest cells. However, expression of the homeobox gene, Msx1, was undetectable in the mesenchyme of dHAND-null branchial arches but unaffected in the limb bud, consistent with the separable regulatory elements of Msx1 previously described. Together, these data suggest a model in which epithelial secretion of ET-1 stimulates mesenchymal expression of dHAND, which regulates Msx1 expression in the growing, distal branchial arch. Complete disruption of this molecular pathway results in growth failure of the branchial arches from apoptosis, while partial disruption leads to defects of branchial arch derivatives, similar to those seen in CATCH-22 syndrome.