ADAMTS18 Deficiency Leads to Pulmonary Hypoplasia and Bronchial Microfibril Accumulation

Abstract

Summary ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) are secreted metalloproteinases that play a major role in the assembly and degradation of the extracellular matrix (ECM). In this study, we show that ADAMTS18, produced by the epithelial cells of distal airways and mesenchymal cells in lung apex at early embryonic stages, serves as a morphogen in lung development. ADAMTS18 deficiency leads to reduced number and length of bronchi, tipped lung apexes, and dilated alveoli. These developmental defects worsen lipopolysaccharide-induced acute lung injury and bleomycin-induced lung fibrosis in adult Adamts18- deficient mice. ADAMTS18 deficiency also causes increased levels of fibrillin1 and fibrillin2, bronchial microfibril accumulation, decreased focal adhesion kinase signaling, and disruption of F-actin organization. Our findings indicate that ECM homeostasis mediated by ADAMTS18 is pivotal in airway branching morphogenesis.

Embigin deficiency leads to delayed embryonic lung development and high neonatal mortality

“…Additionally, many of these genes are potential transcription factors and growth factors in lung development. For example, Scgb3a2 is a growth factor in lung promoting both early and late stages of fetal lung development (Kurotani et al, 2008), Adamts18 is pivotal in airway branching morphogenesis (Lu et al, 2020), and Hmga2 is required for WNT signaling during lung development (Singh et al, 2014). The data suggest that the lack of embigin causes delays rather than structural defects in lung development.…”

Adamts18 modulates the development of the aortic arch and common carotid artery

“…Previous studies showed that some ADAMTS (e.g., ADAMTS-6, ADAMTS-10, and ADAMTS-17) proteases can bind to fibrillin-1 or fibrillin-2 or both (Hubmacher et al, 2017;Cain et al, 2016;Hubmacher and Apte, 2011;Kutz et al, 2011). Recently, we found that Adamts18 modulates bronchial fibrillin microfibril formation by binding to fibrillin-1 (Lu et al, 2020a). In this study, the levels of fibrillin-1 were found to be iScience Article significantly increased in E14.5 CCAs of Adamts18 À/À mice, and Adamts18 À/À CCA was found to have disordered elastic fibers and reduced carotid blood pressure (Figure 5).…”

“…RNA in situ hybridization (ISH) was performed as described previously (Lu et al, 2020a;Zhu et al, 2019). Briefly, mouse embryos were fixed in 10% neutral buffered formalin for 24 h at room temperature (RT) and paraffin-embedded following standard methods.…”

“…ISH was performed on 5-mm-thick sections using the RNAscope 2.5 HD Reagent Kit-RED (Advanced Cell Diagnostics, Hayward, CA). Specific probes were used to detect target mRNAs as described (Lu et al, 2020a;Zhu et al, 2019).…”

“…Schematic illustration of the role of Adamts18 in neural crest cell-derived artery development Adamts18 is a phase-specific gene and is highly expressed at E11.5-E14.5 in cells (mesenchymal cells and fibroblasts) surrounding the embryonic aortic arch (AOAR) and the common carotid artery (CCA) during branchial arch artery development in mice. Adamts18 binds to Fbn1(Lu et al, 2020a) and Fn and cleaves Fn(Ataca et al, 2020). Adamts18 deficiency results in abnormal ECM remodeling, in particular, increased Fn accumulation, thus activating the Notch3 signaling pathway to promote the differentiation of cranial neural crest cells (CNCCs) to vascular smooth muscle cells.…”