Gerhardt Bradley, Leesman Lauren, Burra Kaulini, Snowball John, Rosenzweig Rachel, Guzman Natalie, Ambalavanan Manoj, Sinner Debora
Division of Neonatology and Pulmonary Biology, CCHMC, University of Cincinnati, College of Medicine and University Honors Program, Cincinnati, OH 45229, United States of America.
Dev Biol. 2018 Apr 1;436(1):14-27. doi: 10.1016/j.ydbio.2018.02.002. Epub 2018 Feb 9.
Tracheobronchomalacia (TBM) is a common congenital disorder in which the cartilaginous rings of the trachea are weakened or missing. Despite the high prevalence and clinical issues associated with TBM, the etiology is largely unknown. Our previous studies demonstrated that Wntless (Wls) and its associated Wnt pathways are critical for patterning of the upper airways. Deletion of Wls in respiratory endoderm caused TBM and ectopic trachealis muscle. To understand mechanisms by which Wls mediates tracheal patterning, we performed RNA sequencing in prechondrogenic tracheal tissue of Wls;Shh embryos. Chondrogenic Bmp4, and Sox9 were decreased, while expression of myogenic genes was increased. We identified Notum, a deacylase that inactivates Wnt ligands, as a target of Wls induced Wnt signaling. Notum's mesenchymal ventral expression in prechondrogenic trachea overlaps with expression of Axin2, a Wnt/β-catenin target and inhibitor. Notum is induced by Wnt/β-catenin in developing trachea. Deletion of Notum activated mesenchymal Wnt/β-catenin and caused tracheal mispatterning of trachealis muscle and cartilage as well as tracheal stenosis. Notum is required for tracheal morphogenesis, influencing mesenchymal condensations critical for patterning of tracheal cartilage and muscle. We propose that Notum influences mesenchymal cell differentiation by generating a barrier for Wnt ligands produced and secreted by airway epithelial cells to attenuate Wnt signaling.
气管支气管软化症（TBM）是一种常见的先天性疾病，其中气管软骨环变弱或缺失。尽管TBM的患病率很高且存在临床问题，但其病因在很大程度上尚不清楚。我们之前的研究表明，无翅型MMTV整合位点家族成员（Wls）及其相关的Wnt信号通路对上呼吸道的模式形成至关重要。呼吸内胚层中Wls的缺失导致了TBM和异位气管肌。为了了解Wls介导气管模式形成的机制，我们对Wls;Shh胚胎的软骨形成前气管组织进行了RNA测序。软骨形成相关的骨形态发生蛋白4（Bmp4）和性别决定区Y盒9（Sox9）表达降低，而成肌基因的表达增加。我们鉴定出Notum，一种使Wnt配体失活的去酰基酶，作为Wls诱导的Wnt信号的靶点。Notum在软骨形成前气管中的间充质腹侧表达与Wnt/β-连环蛋白靶点及抑制剂轴抑制蛋白2（Axin2）的表达重叠。Notum在发育中的气管中由Wnt/β-连环蛋白诱导产生。Notum的缺失激活了间充质Wnt/β-连环蛋白信号，并导致气管肌和软骨的气管模式异常以及气管狭窄。Notum是气管形态发生所必需的，影响对气管软骨和肌肉模式形成至关重要的间充质凝聚。我们提出，Notum通过为气道上皮细胞产生和分泌的Wnt配体生成一道屏障来减弱Wnt信号，从而影响间充质细胞分化。
