Syndecan4 coordinates Wnt/JNK and BMP signaling to regulate foregut progenitor development

Temporally and spatially dynamic Wnt and BMP signals are essential to pattern foregut endoderm progenitors that give rise to the liver, pancreas and lungs, but how these two signaling pathways are coordinated in the extracellular space is unknown. Here we identify the transmembrane heparan sulphate proteoglycan Syndecan-4 (Sdc4), as a key regulator of both non-canonical Wnt and BMP signaling in the Xenopus foregut. Foregut-specific Sdc4 depletion results in a disrupted Fibronectin (Fn1) matrix, reduced cell adhesion, and failure to maintain foregut gene expression ultimately leading to foregut organ hypoplasia. Sdc4 is required to maintain robust Wnt/JNK and BMP/Smad1 signaling in the hhex+ foregut progenitors. Pathway analysis suggests that Sdc4 functionally interacts with Fzd7 to promote Wnt/JNK signaling, which maintains foregut identity and cell adhesion. In addition, the Sdc4 ectodomain is required to support Fn1 matrix assembly, which is essential for the robust BMP signaling that promotes foregut gene expression. This work sheds lights on how the extracellular matrix can coordinate different signaling pathways during organogenesis.