Neonatology and Pulmonary Biology Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati Honors Program, Cincinnati, Ohio, United States.
Neonatology and Pulmonary Biology Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States.
Am J Physiol Lung Cell Mol Physiol. 2023 Dec 1;325(6):L788-L802. doi: 10.1152/ajplung.00024.2023. Epub 2023 Oct 24.
Ion channels play critical roles in the physiology and function of the nervous system and contractile tissue; however, their role in noncontractile tissue and embryonic development has yet to be understood. Tracheobronchomalacia (TBM) and complete tracheal rings (CTR) are disorders affecting the muscle and cartilage of the trachea and bronchi, whose etiology remains poorly understood. We demonstrated that trachealis muscle organization and polarity are disrupted after epithelial ablation of (Wls), a cargo receptor critical for the Wnt signaling pathway, in developing trachea. The phenotype resembles the anomalous trachealis muscle observed after deletion of ion channel encoding genes in developing mouse trachea. We sought to investigate whether and how the deletion of affects ion channels during tracheal development. We hypothesize that Wnt signaling influences the expression of ion channels to promote trachealis muscle cell assembly and patterning. Deleting in developing trachea causes differential regulation of genes mediating actin binding, cytoskeleton organization, and potassium ion channel activity. Wnt signaling regulates the expression of , , , and as demonstrated by in vitro studies and in vivo analysis in and β-catenin-deficient tracheas. Pharmacological inhibition of potassium ion channels and Wnt signaling impaired contractility of developing trachealis smooth muscle and formation of cartilaginous mesenchymal condensation. Thus, in mice, epithelial-induced Wnt/β-catenin signaling mediates trachealis muscle and cartilage development via modulation of ion channel expression, promoting trachealis muscle architecture, contractility, and cartilaginous extracellular matrix. In turn, ion channel activity may influence tracheal morphogenesis underlying TBM and CTR. Ion channels play critical roles in the physiology and function of the nervous system and contractile tissue; however, their role in noncontractile tissue and embryonic development has yet to be understood. In this study, we focused on the role of ion channels in the differentiation and patterning of the large airways of the developing respiratory tract. We identify a mechanism by which Wnt-beta-catenin signaling controls levels of ion channel-encoding genes to promote tracheal differentiation.
离子通道在神经系统和收缩组织的生理和功能中起着关键作用；然而，它们在非收缩组织和胚胎发育中的作用尚未被理解。气管支气管软化症（TBM）和完全气管环（CTR）是影响气管和支气管肌肉和软骨的疾病，其病因仍知之甚少。我们证明，上皮细胞消融后，（Wls），Wnt 信号通路的关键货物受体，在发育中的气管中，气管肌组织和极性被破坏。表型类似于在发育中的小鼠气管中删除离子通道编码基因后观察到的异常气管肌。我们试图研究删除是否以及如何影响气管发育过程中的离子通道。我们假设 Wnt 信号影响离子通道的表达，以促进气管肌细胞的组装和模式形成。在发育中的气管中删除会导致介导肌动蛋白结合、细胞骨架组织和钾离子通道活性的基因的差异调节。如体外研究和 Wnt 信号缺失的气管中的体内分析所示，Wnt 信号调节 的表达 ， ， 和 。钾离子通道和 Wnt 信号的药理学抑制损害了发育中的气管平滑肌的收缩性和软骨间充质凝聚的形成。因此，在小鼠中，上皮诱导的 Wnt/β-catenin 信号通过调节离子通道表达介导气管肌和软骨发育，促进气管肌结构、收缩性和软骨细胞外基质。反过来，离子通道活性可能影响 TBM 和 CTR 下的气管形态发生。离子通道在神经系统和收缩组织的生理和功能中起着关键作用；然而，它们在非收缩组织和胚胎发育中的作用尚未被理解。在这项研究中，我们专注于离子通道在发育中呼吸道的大气道分化和模式形成中的作用。我们确定了 Wnt-β-catenin 信号控制离子通道编码基因水平以促进气管分化的机制。
