Signaling pathways crucial for craniofacial development revealed by endothelin-A receptor-deficient mice
Signaling pathways crucial for craniofacial development revealed by endothelin-A receptor-deficient mice
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DOI：
10.1006/dbio.1999.9527
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发表时间：
2000-01-01
影响因子：
2.7
通讯作者：
Yanagisawa, M
中科院分区：
文献类型：
--
作者：
Clouthier, DE;Williams, SC;Yanagisawa, M
颅面区大部分骨和软骨来源于头神经嵴细胞，它们经历了三个主要的发育过程：从异型神经外胚层迁移到咽弓，在咽弓内作为外间质增殖，并分化为末端结构。在这些过程中，外充质细胞和周围细胞之间的相互作用是必需的，在这些过程中，缺陷可能导致颅面畸形。我们之前已经表明，g蛋白偶联内皮素- a受体（ETA）在神经嵴来源的外间充质中表达，而ETA的同源配体内皮素-1 （ET-1）在弓上皮和近轴中胚层来源的弓核中表达；缺乏ETA或ET-1导致大量颅面缺损。在这项研究中，我们试图确定在eta缺陷胚胎中头神经嵴发育中断的点。我们发现，虽然ETA-/-胚胎头部的神经嵴细胞迁移是正常的，但一些转录因子在弓外间充质细胞中的表达要么缺失，要么显著减少。这些依赖于eta的因子包括转录因子goosecoid、Dlx-2、Dlx-3、dHAND、eHAND和Barx1，但不包括MHox、Hoxa-2、CRABP1或Ufd1。此外，E10.5 ~ E11.5 ETA-/-胚胎弓的大小更小，外胚间充质细胞凋亡增加。因此，外间充质细胞中的ETA信号似乎通过诱导迁移后外间充质中转录因子的表达来协调弓发育的特定方面。缺乏这些信号会导致弓生长迟缓，正常分化缺陷，并在一些间充质细胞中导致凋亡。特别是，这种发育途径似乎不同于包括UFD1L在内的途径，UFD1L是CATCH 22患者的致病基因，并表明平行互补途径介导颅面发育。(C) 2000年学术出版社。
Most of the bone and cartilage in the craniofacial region is derived from cephalic neural crest cells, which undergo three primary developmental events: migration from the rhombomeric neuroectoderm to the pharyngeal arches, proliferation as the ectomesenchyme within the arches, and differentiation into terminal structures. Interactions between the ectomesenchymal cells and surrounding cells are required in these processes, in which defects can lead to craniofacial malformation. We have previously shown that the G-protein-coupled endothelin-A receptor (ETA) is expressed in the neural crest-derived ectomesenchyme, whereas the cognate ligand for ETA, endothelin-l (ET-1), is expressed in arch epithelium and the paraxial mesoderm-derived arch core; absence of either ETA or ET-1 results in numerous craniofacial defects. In this study we have attempted to define the point at which cephalic neural crest development is disrupted in ETA-deficient embryos. We find that, while neural crest cell migration in the head of ETA-/- embryos appears normal, expression of a number of transcription factors in the arch ectomesenchymal cells is either absent or significantly reduced. These ETA-dependent factors include the transcription factors goosecoid, Dlx-2, Dlx-3, dHAND, eHAND, and Barx1, but not MHox, Hoxa-2, CRABP1, or Ufd1. In addition, the size of the arches in E10.5 to E11.5 ETA-/- embryos is smaller and an increase in ectomesenchymal apoptosis is observed. Thus, ETA signaling in ectomesenchymal cells appears to coordinate specific aspects of arch development by inducing expression of transcription factors in the postmigratory ectomesenchyme. Absence of these signals results in retarded arch growth, defects in proper differentiation, and, in some mesenchymal cells, apoptosis. In particular, this developmental pathway appears distinct from the pathway that includes UFD1L, implicated as a causative gene in CATCH 22 patients, and suggests parallel complementary pathways mediating craniofacial development. (C) 2000 Academic Press.