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Bone morphogenetic protein (BMP) signaling regulates many different developmental and homeostatic processes in metazoans. The BMP pathway is conserved in Caenorhabditis elegans, and is known to regulate body size and mesoderm development. We have identified the C. elegans smoc-1 (Secreted MOdular Calcium-binding protein-1) gene as a new player in the BMP pathway. smoc-1(0) mutants have a small body size, while overexpression of smoc-1 leads to a long body size and increased expression of the RAD-SMAD (reporter acting downstream of SMAD) BMP reporter, suggesting that SMOC-1 acts as a positive modulator of BMP signaling. Using double-mutant analysis, we showed that SMOC-1 antagonizes the function of the glypican LON-2 and acts through the BMP ligand DBL-1 to regulate BMP signaling. Moreover, SMOC-1 appears to specifically regulate BMP signaling without significant involvement in a TGFβ-like pathway that regulates dauer development. We found that smoc-1 is expressed in multiple tissues, including cells of the pharynx, intestine, and posterior hypodermis, and that the expression of smoc-1 in the intestine is positively regulated by BMP signaling. We further established that SMOC-1 functions cell nonautonomously to regulate body size. Human SMOC1 and SMOC2 can each partially rescue the smoc-1(0) mutant phenotype, suggesting that SMOC-1's function in modulating BMP signaling is evolutionarily conserved. Together, our findings highlight a conserved role of SMOC proteins in modulating BMP signaling in metazoans.
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This content will become publicly available on July 16, 2027
Biochemical principles of SMAD signaling across the animal kingdom
Abstract The bone-morphogenetic protein (BMP)-SMAD signal transduction pathway regulates fundamental cellular processes such as fate specification, tissue patterning, and stem cell homeostasis across metazoans and has a conserved signaling architecture. However, the quantitative dynamics of SMAD signaling and regulatory strategies governing pathway activity show a wide range of variation across developmental and stem-cell systems. In the present review, we summarize insights from six major biological contexts—Drosophila embryo, germline stem cells, and the larval and pupal wing discs; the Danio rerio (zebrafish) embryo; and human pluripotent stem cells—to compare how BMP signals are measured, manipulated, modeled, and integrated. We begin by outlining the canonical BMP signaling pathway and the mechanisms of BMP gradient formation across developmental systems, highlighting how conserved pathway components contribute to the formation of system-specific spatial profiles. We then summarize intracellular Smad dynamics and how endogenous pathway dynamics are measured through quantitative imaging of the phosphorylated Smad. Next, we examine how BMP signaling is interpreted through tiered transcriptional responses of downstream target genes. Next, we summarize the mechanistic and computational models of integrated gradient formation, signal transduction, and gene regulation across the presented systems. These insights reveal unifying design principles and performance objectives that govern BMP-SMAD signaling across species and cell types and frame open questions for future cross-species and translational studies.
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- PAR ID:
- 10702290
- Publisher / Repository:
- Portland Press
- Date Published:
- Journal Name:
- Biochemical Journal
- Volume:
- 483
- Issue:
- 8
- ISSN:
- 0264-6021
- Page Range / eLocation ID:
- 1509 to 1534
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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