BMP pathway regulation of insulin signaling components promotes lipid storage in Caenorhabditis elegans.

A small number of peptide growth factor ligands are used repeatedly in development and homeostasis to drive programs of cell differentiation and function. Cells and tissues must integrate inputs from these diverse signals correctly, while failure to do so leads to pathology, reduced fitness, or death. Previous work using the nematode C. elegans identified an interaction between the bone morphogenetic protein (BMP) and insulin/IGF-1-like signaling (IIS) pathways in the regulation of lipid homeostasis. The molecular components required for this interaction, however, were not fully understood. Here we report that INS-4, one of 40 insulin-like peptides (ILPs), is regulated by BMP signaling to modulate fat accumulation. Furthermore, we find that the IIS transcription factor DAF-16/FoxO, but not SKN-1/Nrf, acts downstream of BMP signaling in lipid homeostasis. Interestingly, BMP activity alters sensitivity of these two transcription factors to IIS-promoted cytoplasmic retention in opposite ways. Finally, we probe the extent of BMP and IIS interactions by testing additional IIS functions including dauer formation, aging, and autophagy induction. Coupled with our previous work and that of other groups, we conclude that BMP and IIS pathways have at least three modes of interaction: independent, epistatic, and antagonistic. The molecular interactions we identify provide new insight into mechanisms of signaling crosstalk and potential therapeutic targets for IIS-related pathologies such as diabetes and metabolic syndrome.

Feedback regulation of BMP signaling by Caenorhabditis elegans cuticle collagens.

Cellular responsiveness to environment, including changes in extracellular matrix (ECM), is critical for normal processes such as development and wound healing, but can go awry, as in oncogenesis and fibrosis. One type of molecular pathway contributing to this responsiveness is the BMP signaling pathway. Owing to their broad and potent functions, BMPs and their pathways are regulated at multiple levels. In Caenorhabditis elegans, the BMP ligand DBL-1 is a regulator of body size. We previously showed that DBL-1/BMP signaling determines body size through transcriptional regulation of cuticle collagen genes. We now identify feedback regulation of DBL-1/BMP through analysis of four DBL-1-regulated collagen genes. Inactivation of any of these genes reduces DBL-1/BMP signaling, measured by a pathway activity reporter. Furthermore, depletion of these collagens reduces GFP::DBL-1 fluorescence and acts unexpectedly at the level of dbl-1 transcription. We conclude that cuticle, a specialized ECM, impinges on DBL-1/BMP expression and signaling. Interestingly, the feedback regulation of DBL-1/BMP signaling by collagens is likely to be contact independent due to physical separation of the cuticle from DBL-1-expressing cells in the ventral nerve cord. Our results provide an entry point into a novel regulatory mechanism for BMP signaling, with broader implications for mechanical regulation of gene expression.