Disrupted endosomal trafficking of the Vangl-Celsr polarity complex causes congenital anomalies in trachea-esophageal separation.

The developmental basis of esophageal atresia and tracheoesophageal fistulas (EA/TEF), life-threatening congenital anomalies where the embryonic foregut fails to properly separate into trachea and esophagus, is poorly understood. Recent genome sequencing reveals that de novo variants in intracellular trafficking genes are enriched in EA/TEF patients, suggesting that these cellular processes regulate foregut morphogenesis. Here we show that mutation of orthologous genes in Xenopus disrupts trachea-esophageal separation like EA/TEF patients. We identify the underlying mechanism showing that the Rab11a recycling endosome pathway is required to localize Vangl-Celsr polarity complexes at the apical cell surface where opposite sides of the foregut tube fuses forming a transient epithelial bilayer. A partial loss of endosome trafficking or knockdown of the Vangl/Celsr complex disrupts cell polarity and planar cell division. Mutant cells accumulate in the disorganize septum, 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.