Wnt5a和Notum影响发育中气管软骨间充质凝集的时间动态

Natalia Bottasso-Arias, Megha Mohanakrishnan, Sarah Trovillion, Kaulini Burra, Nicholas Russell, Yixin Wu, Yan Xu, Debora I Sinner
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摘要

气管对气流正常进入肺部进行气体交换至关重要。频繁发生的先天性气管畸形会影响软骨,导致呼吸周期中的中央气道塌陷。我们的研究表明,Notum 是一种 Wnt 配体脱乙酰化酶,它能减弱 Wnt 信号通路的典型分支,是软骨间充质凝聚所必需的。在缺乏 Notum 的气管中,软骨形成延迟,气管腔变窄。目前还不清楚Notum是否会减弱非经典Wnt信号转导。值得注意的是,我们观察到在间质删除非经典 Wnt5a 配体后,气管软骨形成过早。我们推测,Notum 和 Wnt5a 需要介导间质凝聚的及时形成,从而产生气管软骨。气管组织的体内外培养显示,对 Wnt 非规范途径的化学抑制可促进更早的凝结,而对 Notum 的抑制则会延迟凝结。此外,非经典 Wnt 诱导可阻止软骨间充质凝聚的形成。另一方面,在缺乏间质 Wnt5a 的情况下,软骨母细胞之间的细胞间相互作用会增加。通过对Wnt5a和Notum缺陷气管中的基因表达进行无偏分析,我们发现在Wnt5a突变体中,对软骨形成和细胞外基质形成至关重要的基因的mRNA在E11.5时上调。这一表达谱支持了在Wnt5a和Notum缺陷气管中分别观察到的过早和延迟的软骨形成。我们的结论是,Notum 和 Wnt5a 是通过协调及时的软骨形成来实现适当的气管软骨形态的必要条件。因此,这些研究揭示了气管先天性异常的分子机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Wnt5a and Notum Influence the Temporal Dynamics of Cartilaginous Mesenchymal Condensations in Developing Trachea.
The trachea is essential for proper airflow to the lungs for gas exchange. Frequent congenital tracheal malformations affect the cartilage, causing the collapse of the central airway during the respiratory cycle. We have shown that Notum, a Wnt ligand de-acylase that attenuates the canonical branch of the Wnt signaling pathway, is necessary for cartilaginous mesenchymal condensations. In Notum deficient tracheas, chondrogenesis is delayed, and the tracheal lumen is narrowed. It is unknown if Notum attenuates non-canonical Wnt signaling. Notably, we observed premature tracheal chondrogenesis after mesenchymal deletion of the non-canonical Wnt5a ligand. We hypothesize that Notum and Wnt5a are required to mediate the timely formation of mesenchymal condensations, giving rise to the tracheal cartilage. Ex vivo culture of tracheal tissue shows that chemical inhibition of the Wnt non-canonical pathway promotes earlier condensations, while Notum inhibition presents delayed condensations. Furthermore, non-canonical Wnt induction prevents the formation of cartilaginous mesenchymal condensations. On the other hand, cell-cell interactions among chondroblasts increase in the absence of mesenchymal Wnt5a. By performing an unbiased analysis of the gene expression in Wnt5a and Notum deficient tracheas, we detect that mRNA of genes essential for chondrogenesis and extracellular matrix formation are upregulated by E11.5 in Wnt5a mutants. The expression profile supports the premature and delayed chondrogenesis observed in Wnt5a and Notum deficient tracheas, respectively. We conclude that Notum and Wnt5a are necessary for proper tracheal cartilage patterning by coordinating timely chondrogenesis. Thus, these studies shed light on molecular mechanisms underlying congenital anomalies of the trachea.
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