Thomas T, Kurihara H, Yamagishi H, Kurihara Y, Yazaki Y, Olson E N, Srivastava D
Department of Pediatrics, Division of Cardiology and Department of Molecular Biology and Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9148, USA. edu.
Development. 1998 Aug;125(16):3005-14. doi: 10.1242/dev.125.16.3005.
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.
许多人类综合征是颅神经嵴发育异常的结果。其中一组这样的缺陷，称为CATCH-22（心脏缺陷、面容异常、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，表现出颅面和心脏缺陷，这是由于第三和第四神经嵴衍生的鳃弓和鳃弓动脉发育异常所致。携带内皮素-1基因（Edn1）无效突变的小鼠，该基因在鳃弓的上皮层表达并编码内皮素-1（ET-1）信号肽，其表型类似于CATCH-22综合征，伴有主动脉弓缺陷和颅面异常。在这里，我们表明基本螺旋-环-螺旋转录因子dHAND在鳃弓上皮下方的间充质中表达。此外，dHAND和相关基因eHAND在Edn1无效胚胎的鳃弓和主动脉弓中表达下调。在dHAND基因纯合缺失的小鼠中，第一和第二鳃弓因程序性细胞死亡而发育不全，第三和第四鳃弓未能形成。分子分析表明，鳃弓神经嵴衍生成分的大多数标志物在dHAND缺失的胚胎中表达，表明神经嵴细胞迁移正常。然而，同源盒基因Msx1在dHAND缺失的鳃弓间充质中无法检测到，但在肢芽中不受影响，这与先前描述的Msx1的可分离调控元件一致。总之，这些数据表明了一种模型，其中ET-1的上皮分泌刺激dHAND的间充质表达，dHAND调节生长中的远端鳃弓中Msx1的表达。该分子途径的完全破坏导致鳃弓因细胞凋亡而生长失败，而部分破坏则导致鳃弓衍生物的缺陷，类似于CATCH-22综合征中所见的缺陷。
