Hedgehog and WNT Signaling Hubs in Tracheal Morphogenesis.
Hedgehog and WNT Signaling Hubs in Tracheal Morphogenesis.
复制标题
Hedgehog 和 WNT 信号中枢在气管形态发生中的作用。
DOI：
10.1164/rccm.201907-1285ed
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发表时间：
2019
影响因子：
24.7
通讯作者：
Morrisey,EdwardE
中科院分区：
文献类型：
--
作者：
Frank,DavidB;Morrisey,EdwardE
气管提供了从呼吸系统到外部环境的直接管道。在哺乳动物中，气管被软骨环包围，这些软骨环执行多种功能，包括提供结构支撑和保持气管开放。已经使用遗传小鼠模型探索了气管的发育，这些模型揭示了多种旁分泌信号传导途径的重要性，例如SHH（音刺猬）和WNT（无翼相关整合位点）途径（1-4）。在人类中，气管缺陷在儿科患者人群中很常见，包括气管软化和更罕见的疾病完全气管环畸形（CTRD）等缺陷（5，6）。在CTRD中，气管周围的软骨环是完整的，缺乏气管肌填充的背侧间隙。与其他孤儿疾病一样，CTRD的致病机制一直困扰着研究人员，因为这些疾病的组织和代表性动物模型缺乏。因此，人们经常不清楚人类致病突变是否遵循与遗传小鼠模型中发现的分子途径相似的分子途径。在本期杂志中，Sinner及其同事（pp. 1267-1281）揭示了导致CTRD的多种人类遗传病变，包括SHH途径内的基因突变和WNT途径内的多个基因突变，包括ROR 2（受体酪氨酸激酶样孤儿受体2）（7）（图1）。这项研究强调了小鼠呼吸发育模型与人类先天性气管异常之间的密切关系，并提供了在人类气管发育中发挥重要作用的新靶基因和途径。气管最初从前肠发育而来。随后，间充质-上皮串扰建立了WNT和BMP（骨形态发生蛋白）信号传导的腹-背梯度，以分别促进气管和食管的适当规格、模式化和分离（1，2，8，9）。沿着WNT和BMP信号传导，SHH信号传导已显示在气管和食管的分离中以及在促进呼吸系统内的气管和其它区域中的间充质衍生物的适当分化中起重要作用（3，4，10）。分离发生后，气管内的软骨祖细胞由转录因子SOX 9的表达表示，SOX 9既是软骨发育的标志物，也是软骨发育的功能调节剂（11）。这些祖细胞的发育缺陷可导致不能形成围绕气管的气管软骨环。Sinner及其同事对CTRD患者沿着父母进行了全外显子组测序的三重分析，以确定新的突变（7）。值得注意的是，许多突变涉及WNT或SHH通路。这些包括遗传和自发突变。WNT途径中的突变，包括ROR 2和LRRC 7（富含亮氨酸的重复序列，含有7），涉及b-连环蛋白依赖性（LRRC 7）和b-连环蛋白非依赖性（ROR 2）途径。在SHH中发现了新生突变，在HSPG 2中观察到了复合杂合突变，HSPG 2是一种细胞外硫酸肝素蛋白聚糖，已知可调节SHH和其他旁分泌途径（12）。先前在小鼠中的研究已经证明了WNT和SHH在呼吸系统（包括气管）内多个组织的发育中的重要作用。SHH的缺失也会导致气管软骨形成失败（10）。由于SHH仅在发育中的呼吸内胚层中表达，这表明...
The trachea provides a direct conduit from the respiratory system to the external environment. In mammals, the trachea is surrounded by cartilaginous rings that perform several duties, including providing structural support and keeping the trachea patent. The development of the trachea has been explored using genetic mouse models that reveal the importance of multiple paracrine signaling pathways, such as the SHH (sonic hedgehog) and WNT (Wingless-related integration site) pathways (1–4). In humans, tracheal defects are common in the pediatric patient population and include defects such as tracheomalacia and the rarer disease, complete tracheal ring deformity (CTRD)(5, 6). In CTRD, the cartilaginous rings surrounding the trachea are complete and lack a dorsal gap filled in with the trachealis muscle. As with other orphan diseases, the pathogenic mechanisms of CTRD have eluded investigators given the paucity of tissue and representative animal models of these diseases. As such, it is frequently unclear whether disease-causing mutations in humans follow molecular pathways similar to those discovered in genetic mouse models. In this issue of the Journal, Sinner and colleagues (pp. 1267–1281) uncover multiple human genetic lesions that lead to CTRD, including mutations in genes within the SHH pathway and mutations in multiple genes within the WNT pathway, including ROR2 (receptor tyrosine kinase–like orphan receptor 2)(7)(Figure 1). This study highlights the close relationship between mouse models of respiratory development and human congenital tracheal abnormalities, and it provides new target genes and pathways that play an important role in tracheal development in humans. The trachea initially develops from the anterior foregut. Subsequently, mesenchymal–epithelial cross-talk sets up a ventral–dorsal gradient of WNT and BMP (bone morphogenetic protein) signaling to promote the proper specification, patterning, and separation of the trachea and esophagus, respectively (1, 2, 8, 9). Along with WNT and BMP signaling, SHH signaling has been show to play important roles in separation of the trachea and esophagus, as well as in promoting proper differentiation of mesenchymal derivatives in the trachea and other regions within the respiratory system (3, 4, 10). After separation occurs, the cartilaginous progenitors within the trachea are denoted by expression of the transcription factor SOX9, which is both a marker and functional regulator of cartilage development (11). Defects in the development of these progenitors can lead to failure to form the tracheal cartilaginous rings surrounding the trachea. Sinner and colleagues performed a trio analysis with whole-exome sequencing of patients with CTRD along with their parents to identify novel mutations (7). Remarkably, many of the mutations implicated either the WNT or SHH pathway. These included both heritable and spontaneous mutations. The mutations in the WNT pathway, including ROR2 and LRRC7 (leucine rich repeat containing 7), involve both b-catenin–dependent (LRRC7) and b-catenin–independent (ROR2) pathways. De novo mutations were found in SHH, and compound heterozygous mutations were observed in HSPG2, an extracellular heparin sulfate proteoglycan that is known to modulate SHH and other paracrine pathways (12). Previous studies in mice have demonstrated important roles for WNT and SHH in the development of multiple tissues within the respiratory system, including the trachea. Loss of SHH also leads to failure of tracheal cartilage formation (10). As SHH is expressed exclusively within the developing respiratory endoderm, this suggests …