Disrupted endosomal trafficking of the Vangl-Celsr polarity complex underlies congenital anomalies in trachea-esophageal morphogenesis

Edwards NA, Kashyap A, Warren A, Agricola ZN, Kenny AP, Shen Y, Chung WK, Zorn AM

bioRxiv, 2023.

Lab members marked as bold


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 de novo variants in intracellular trafficking genes are enriched in EA/TEF patients. Here we show that mutation of orthologous genes in Xenopus 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 cell surface where opposite sides of the common foregut tube fuse. Partial loss of endosome trafficking or the Vangl/Celsr complex disrupts epithelial polarity and cell division orientation. Mutant cells accumulate at the fusion point, fail to downregulate cadherin, and do not separate into distinct trachea and esophagus. These data provide new insights into the mechanisms of congenital anomalies and general paradigms of tissue fusion during organogenesis.