Center for Human Genetics, Marburg University and Marburg University Hospital, Marburg, Germany.
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, USA.
Sci Rep. 2024 Feb 14;14(1):3752. doi: 10.1038/s41598-024-53098-w.
Understanding the molecular mechanisms of congenital diseases is challenging due to their occurrence within specific developmental stages. Esophageal malformations are examples of such conditions, characterized by abnormalities in the development of esophagus during embryogenesis. These developmental malformations encompass a range of anomalies, including esophageal atresia, and tracheoesophageal fistula. Here, we investigated the preferential expression of 29 genes that are implicated in such malformations and their immediate interactome (a total of 67 genes). We conducted our analyses across several single-cell atlases of embryonic development, encompassing approximately 150,000 cells from the mouse foregut, 180,000 cells from human embryos, and 500,000 cells from 24 human organs. Our study, spanning diverse mesodermal and endodermal cell populations and early developmental stages, shows that the genes associated with esophageal malformations show their highest cell-type specific expression in lateral plate mesoderm cells and at the developmental stage of E8.75-E9.0 days. In human embryos, these genes show a significant cell-type specific expression among subpopulations of epithelial cells, fibroblasts and progenitor cells including basal cells. Notably, members of the forkhead-box family of transcription factors, namely FOXF1, FOXC1, and FOXD1, as well as the SRY-box transcription factor, SOX2, demonstrate the most significant preferential expression in both mouse and human embryos. Overall, our findings provide insights into the temporal and cellular contexts contributing to esophageal malformations.
了解先天性疾病的分子机制具有挑战性，因为它们发生在特定的发育阶段。食管畸形就是这种情况的一个例子，其特征是胚胎发生过程中食管发育异常。这些发育畸形包括食管闭锁和气管食管瘘等多种异常。在这里，我们研究了 29 个与这些畸形及其直接相互作用组（共 67 个基因）相关的基因的优先表达。我们在几个胚胎发育的单细胞图谱中进行了分析，涵盖了大约 150000 个来自小鼠前肠的细胞、180000 个人类胚胎细胞和 500000 个来自 24 个人类器官的细胞。我们的研究跨越了不同的中胚层和内胚层细胞群和早期发育阶段，表明与食管畸形相关的基因在侧中胚层细胞和 E8.75-E9.0 天的发育阶段表现出最高的细胞类型特异性表达。在人类胚胎中，这些基因在包括基底细胞在内的上皮细胞、成纤维细胞和祖细胞的亚群中表现出显著的细胞类型特异性表达。值得注意的是，叉头框转录因子家族的成员 FOXF1、FOXC1 和 FOXD1 以及 Sry 盒转录因子 SOX2 在小鼠和人类胚胎中均表现出最显著的优先表达。总的来说，我们的研究结果提供了对食管畸形形成的时间和细胞背景的深入了解。
