Edwards Nicole A, Rankin Scott A, Kashyap Adhish, Warren Alissa, Agricola Zachary N, Kenny Alan P, Kofron Matthew J, Shen Yufeng, Chung Wendy K, Zorn Aaron M
bioRxiv. 2024 Dec 2:2023.10.11.561909. doi: 10.1101/2023.10.11.561909.
Disruptions in foregut morphogenesis can result in life-threatening conditions where the trachea and esophagus fail to separate properly, such as esophageal atresia (EA) and tracheoesophageal fistulas (TEF). The developmental basis of these congenital anomalies is poorly understood, but recent genome sequencing reveals that variants in intracellular trafficking genes are enriched in EA/TEF patients. Here, we confirm that mutation of orthologous genes in disrupts trachea-esophageal separation similar to EA/TEF patients. We show that the Rab11a recycling endosome pathway is required to localize Vangl-Celsr polarity complexes at the luminal cell surface where opposite sides of the foregut tube fuse. Partial loss of endosome trafficking or Vangl-Celsr complexes disrupts epithelial polarity and mutant cells accumulate at the fusion point, fail to downregulate Cadherin, and do not separate into distinct trachea and esophagus. These data provide insights into the mechanisms of congenital anomalies and general paradigms of tissue fusion during organogenesis.
前肠形态发生的破坏可导致危及生命的情况，即气管和食管无法正常分离，如食管闭锁（EA）和气管食管瘘（TEF）。这些先天性异常的发育基础尚不清楚，但最近的基因组测序显示，细胞内运输基因的变异在EA/TEF患者中富集。在这里，我们证实，与EA/TEF患者相似，直系同源基因的突变会破坏气管-食管分离。我们表明，Rab11a循环内体途径是将Vangl-Celsr极性复合物定位在前肠管相对两侧融合处的腔面细胞表面所必需的。内体运输或Vangl-Celsr复合物的部分缺失会破坏上皮极性，突变细胞在融合点积聚，无法下调钙黏蛋白，也不会分离成不同的气管和食管。这些数据为先天性异常的机制以及器官发生过程中组织融合的一般模式提供了见解。
