Russell Nicholas X, Burra Kaulini, Shah Ronak, Bottasso-Arias Natalia, Mohanakrishnan Megha, Snowball John, Ediga Harshavardhana H, Madala Satish K, Sinner Debora
Neonatology and Pulmonary Biology Perinatal Institute. Cincinnati Children's Hospital Medical Center and University of Cincinnati Honors Program.
Neonatology and Pulmonary Biology Perinatal Institute. Cincinnati Children's Hospital Medical Center. Current affiliation: Nationwide Children's Hospital Columbus OH.
bioRxiv. 2023 Aug 24:2023.01.10.523309. doi: 10.1101/2023.01.10.523309.
Ion channels play critical roles in the physiology and function of the nervous system and contractile tissue; however, their role in non-contractile 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 regulated expression of and as demonstrated by in vitro studies and in vivo analysis in and β- 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.
离子通道在神经系统和收缩组织的生理及功能中发挥着关键作用；然而，它们在非收缩组织和胚胎发育中的作用尚未明确。气管软化症（TBM）和完全气管环（CTR）是影响气管和支气管肌肉及软骨的疾病，其病因仍知之甚少。我们证明，在发育中的气管中，对Wnt信号通路至关重要的货物受体Wls上皮消融后，气管平滑肌的组织和极性会受到破坏。该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平滑肌。我们试图研究Wls的缺失在气管发育过程中是否以及如何影响离子通道。我们假设Wnt信号影响离子通道的表达，以促进气管平滑肌细胞的组装和模式形成。在发育中的气管中删除Wls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出现差异调节。体外研究以及Wls和β-连环蛋白缺陷气管的体内分析表明，Wnt信号调节了相关基因的表达。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以及软骨间充质凝聚的形成。因此，在小鼠中，上皮诱导的Wnt/β-连环蛋白信号通过调节离子通道表达介导气管平滑肌和软骨发育，促进气管平滑肌结构、收缩性以及软骨细胞外基质的形成。反过来，离子通道活性可能影响TBM和CTR潜在的气管形态发生。
