Xenopus SMOC-1 Inhibits bone morphogenetic protein signaling downstream of receptor binding and is essential for postgastrulation development in Xenopus.
The bone morphogenetic protein (BMP) family of signaling molecules and their antagonists are involved in patterning of the body axis and numerous aspects of organogenesis. Classical biochemical purification and protein sequencing of highly purified fractions containing potent bone forming activity from bovine cartilage identified several BMPs together with a number of other proteins. One such protein was SMOC-2 (secreted modular calcium-binding protein-2), classified as belonging to the BM-40 family of modular extracellular proteins. Data regarding the biological function of SMOC-2 and closely related SMOC-1 remain limited, and their expression or function during embryological development is unknown. We therefore isolated the Xenopus ortholog of human SMOC-1 (XSMOC-1) and explored its function in Xenopus embryos. In gain-of-function assays, XSMOC-1 acted similarly to a BMP antagonist. However, in contrast to known extracellular ligand-binding BMP antagonists, such as noggin, SMOC antagonizes BMP activity in the presence of a constitutively active BMP receptor, indicating a mechanism of action downstream of the receptor. We provide several lines of evidence to suggest that SMOC acts downstream of the BMP receptor via MAPK-mediated phosphorylation of the Smad linker region. Loss-of-function studies, using antisense morpholino oligonucleotides, revealed XSMOC-1 to be essential for postgastrulation development. The catastrophic developmental failure observed following XSMOC knockdown resembles that observed following simultaneous depletion of three ligand-binding BMP antagonists described in prior studies. These findings provide a direct link between the extracellular matrix-associated protein SMOC and a signaling pathway of general importance in anatomic patterning and cell or tissue fate specification.
Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Bethesda, Maryland 20892, USA. john.thomas@fda.hhs.gov
J Terrig
JT
Thomas
Paola
P
Canelos
Frank P
FP
Luyten
Malcolm
M
Moos
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D015676:Osteonectin / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014981:Xenopus; D029867:Xenopus Proteins / Q000096:biosynthesis / Q000502:physiology*; D014982:Xenopus laevis; D015027:Zebrafish
D019485:Bone Morphogenetic Proteins; D008024:Ligands; D016376:Oligonucleotides, Antisense; D015676:Osteonectin; C524549:SMOC-1 protein, mouse; C543141:SMOC1 protein, Xenopus; D029867:Xenopus Proteins