Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad-CIRM Center for Regenerative Medicine and Stem Cell Research, W.M. Keck School of Medicine of the University of Southern California, CA, 90089, USA.
Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia; Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
Dev Biol. 2019 Oct 15;454(2):156-169. doi: 10.1016/j.ydbio.2019.06.012. Epub 2019 Jun 23.
Adamts18 encodes a secreted metalloprotease restricted to branch-tip progenitor pools directing the morphogenesis of multiple mammalian organs. Adamts18 was targeted to explore a potential role in branching morphogenesis. In the kidney, an arborized collecting system develops through extensive branching morphogenesis of an initial epithelial outgrowth of the mesonephric duct, the ureteric bud. Adamts18 mutants displayed a weakly penetrant phenotype: duplicated ureteric outgrowths forming enlarged, bi-lobed kidneys with an increased nephron endowment. In contrast, Adamts18 mutants showed a fully penetrant lung phenotype: epithelial growth was markedly reduced and early secondary branching scaled to the reduced length of the primary airways. Furthermore, there was a pronounced delay in the appearance of differentiated cell types in both proximal and distally positions of the developing airways. Adamts18 is closely related to Adamts16. In the kidney but not the lung, broad epithelial Adamts16 expression overlaps Adamts18 in branch tips. However, compound Adamts16/18 mutants displayed a comparable low penetrance duplicated ureteric phenotype, ruling out a possible role for Adamts16 as a functional modifier of the Adamts18 kidney phenotype. Given the predicted action of secreted Adamts18 metalloprotease, and broad expression of Adamts18 in branching organ systems, these findings suggest distinct requirements for matrix modelling in the morphogenesis of epithelial networks.
Adamts18 编码一种分泌型金属蛋白酶，仅限于分支尖端祖细胞池，指导多种哺乳动物器官的形态发生。靶向 Adamts18 以探索其在分支形态发生中的潜在作用。在肾脏中，通过中肾管的输尿管芽的初始上皮外生的广泛分支形态发生，形成分支的收集系统。Adamts18 突变体表现出弱穿透表型：输尿管外生的重复形成增大的双叶肾脏，肾单位增多。相比之下，Adamts18 突变体显示出完全穿透的肺表型：上皮生长明显减少，早期次级分支按初级气道的缩短比例缩小。此外，在发育中的气道的近端和远端位置，分化细胞类型的出现明显延迟。Adamts18 与 Adamts16 密切相关。在肾脏中，但不在肺部，广泛的上皮 Adamts16 表达与分支尖端的 Adamts18 重叠。然而，复合 Adamts16/18 突变体显示出类似的低穿透性重复输尿管表型，排除了 Adamts16 作为 Adamts18 肾脏表型的功能修饰因子的可能性。鉴于分泌型 Adamts18 金属蛋白酶的预期作用以及 Adamts18 在分支器官系统中的广泛表达，这些发现表明在上皮网络形态发生中对基质建模有不同的要求。
