Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
Development. 2024 Aug 15;151(16). doi: 10.1242/dev.202692. Epub 2024 Sep 3.
Adult mammalian lungs exhibit a fractal pattern, as each successive generation of airways is a fraction of the size of the parental branch. Achieving this structure likely requires precise control of airway length and diameter, as the embryonic airways initially lack the fractal scaling observed in the adult. In monolayers and tubes, directional growth can be regulated by the planar cell polarity (PCP) complex. Here, we characterized the roles of PCP complex components in airway initiation, elongation and widening during branching morphogenesis of the lung. Using tissue-specific knockout mice, we surprisingly found that branching morphogenesis proceeds independently of PCP complex function in the lung epithelium. Instead, we found a previously unreported Celsr1-independent role for the PCP complex components Vangl1 and Vangl2 in the pulmonary mesenchyme, where they are required for branch initiation, elongation and widening. Our data thus reveal an explicit function for Vangl1 and Vangl2 that is independent of the core PCP complex, suggesting a functional diversification of PCP complex components in vertebrate development. These data also reveal an essential role for the embryonic mesenchyme in generating the fractal structure of airways in the mature lung.
成年哺乳动物的肺部呈现出分形模式，因为每一代新的气道都是其亲本分支的一小部分。实现这种结构可能需要精确控制气道的长度和直径，因为胚胎气道最初缺乏成人气道的分形比例。在单层和管中，定向生长可以通过平面细胞极性（PCP）复合物来调节。在这里，我们描述了 PCP 复合物成分在肺分支形态发生过程中气道起始、伸长和增宽中的作用。使用组织特异性敲除小鼠，我们惊讶地发现，分支形态发生过程不依赖于肺上皮中的 PCP 复合物功能。相反，我们发现 PCP 复合物成分 Vangl1 和 Vangl2 在肺间质中具有以前未报道的 Celsr1 非依赖性作用，它们是分支起始、伸长和增宽所必需的。因此，我们的数据揭示了 Vangl1 和 Vangl2 的明确功能，该功能独立于核心 PCP 复合物，这表明 PCP 复合物成分在脊椎动物发育中的功能多样化。这些数据还揭示了胚胎间质在成熟肺部气道的分形结构生成中的重要作用。
