MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Molecular Pathology, Department of Laboratory Medicine, Royal Infirmary of Edinburgh, 51 Little France Crescent, Old Dalkeith Road, Edinburgh EH16 4SA, UK.
Dis Model Mech. 2021 Jan 26;14(1):dmm046797. doi: 10.1242/dmm.046797.
Congenital diaphragmatic hernia (CDH) is a relatively common developmental defect with considerable mortality and morbidity. Formation of the diaphragm is a complex process that involves several cell types, each with different developmental origins. Owing to this complexity, the aetiology of CDH is not well understood. The pleuroperitoneal folds (PPFs) and the posthepatic mesenchymal plate (PHMP) are transient structures that are essential during diaphragm development. Using several mouse models, including lineage tracing, we demonstrate the heterogeneous nature of the cells that make up the PPFs. The conditional deletion of Wilms tumor 1 homolog () in the non-muscle mesenchyme of the PPFs results in CDH. We show that the fusion of the PPFs and the PHMP to form a continuous band of tissue involves movements of cells from both sources. The PPFs of mutant mice fail to fuse with the PHMP and exhibit increased RALDH2 (also known as ALDH1A2) expression. However, no changes in the expression of genes (including , , and ) implicated in epithelial-to-mesenchymal transition are observed. Additionally, the mutant PPFs lack migrating myoblasts and muscle connective tissue fibroblasts (TCF4/GATA4), suggesting possible interactions between these cell types. Our study demonstrates the importance of the non-muscle mesenchyme in development of the diaphragm.
先天性膈疝 (CDH) 是一种相对常见的发育缺陷，具有相当高的死亡率和发病率。膈肌的形成是一个复杂的过程，涉及到几种细胞类型，每种细胞都有不同的发育来源。由于这种复杂性，CDH 的病因尚不清楚。胸腹膜褶 (PPFs) 和肝后间充质板 (PHMP) 是在膈肌发育过程中起关键作用的暂时性结构。我们使用包括谱系追踪在内的几种小鼠模型，证明了构成 PPFs 的细胞具有异质性。在 PPFs 的非肌肉间质中条件性删除 Wilms 肿瘤 1 同源物 () 会导致 CDH。我们表明，PPFs 与 PHMP 的融合形成连续的组织带涉及来自两个来源的细胞的运动。突变小鼠的 PPFs 未能与 PHMP 融合，并表现出 RALDH2（也称为 ALDH1A2）表达增加。然而，未观察到参与上皮间质转化的基因（包括 、 、 和 ）表达发生变化。此外，突变的 PPFs 缺乏迁移的成肌细胞和肌肉结缔组织成纤维细胞（TCF4/GATA4），表明这些细胞类型之间可能存在相互作用。我们的研究表明，非肌肉间质在膈肌发育中的重要性。
