title: Sizzled-tolloid interactions maintain foregut progenitors by regulating fibronectin-dependent BMP signaling.
abstract: 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.
authors.affiliation: Perinatal Institute, Cincinnati Children's Research Foundation, Cincinnati, OH 45229, USA. alan.kenny@cchmc.org
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kenny
authors.forename: Scott A
authors.initials: SA
authors.lastname: Rankin
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Allbee
authors.forename: Allison R
authors.initials: AR
authors.lastname: Prewitt
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Meredith E
authors.initials: ME
authors.lastname: Tabangin
authors.forename: Emily T
authors.initials: ET
authors.lastname: Shifley
authors.forename: Mariana P
authors.initials: MP
authors.lastname: Louza
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Zorn
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D019070:Cell Lineage; D004622:Embryo, Mammalian / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000196:embryology; D011485:Protein Binding; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D055394:Tolloid-Like Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D005353:Fibronectins; D029867:Xenopus Proteins; C109976:szl protein, Xenopus; D055394:Tolloid-Like Metalloproteinases; C575919:tll1 protein, Xenopus