Sizzled-Tolloid Interactions Maintain Foregut Progenitors by Regulating Fibronectin-Dependent BMP Signaling

The liver, pancreas, and lungs are induced from endoderm progenitors by a series of dynamic growth factor signals from the mesoderm, but how the temporal-spatial activity of these signals is controlled is poorly understood. We have identified an extracellular regulatory loop required for robust bone morphogenetic protein (BMP) signaling in the Xenopus foregut. We show that BMP signaling is required to maintain foregut progenitors and induce expression of the secreted frizzled related protein Sizzled (Szl) and the extracellular metalloprotease Tolloid-like 1 (Tll1). Szl negatively regulates Tll activity to control deposition of a fibronectin (FN) matrix between the mesoderm and endoderm, which is required to maintain BMP signaling. Foregut-specific Szl depletion results in a loss of the FN matrix and failure to maintain robust pSmad1 levels, causing a loss of foregut gene expression and organ agenesis. These results have implications for BMP signaling in diverse contexts and the differentiation of foregut tissue from stem cells. [Display omitted] ► Sizzled exerts a pro-BMP activity required to maintain Xenopus foregut progenitors ► Szl negatively regulates Tolloid-like proteases to modulate the fibronectin matrix ► The fibronectin matrix is required to maintain robust BMP signaling in the foregut ► Szl-Tll interactions regulate a fibronectin-dependent BMP signaling loop Mechanisms controlling signaling dynamics during foregut organogenesis are poorly understood. Kenny et al. show that, in Xenopus, the Sfrp Sizzled inhibits Tolloid-like proteases to fine-tune fibronectin matrix assembly between the mesoderm and endoderm. This regulation is required for the robust bone morphogenetic protein signaling that is essential to maintain foregut progenitors.