TGF-beta Signaling Mechanisms in C. elegans Physiology and Homeostasis

Project Summary The Transforming Growth Factor beta (TGF-β) family of secreted peptide growth factors plays significant roles in cell function, tissue patterning, and organismal homeostasis. Dysregulation of TGF-β signaling pathways is associated with many diseases and disorders, including cancer, cardiovascular disease, and developmental disorders. These ligands can be divided into bone morphogenetic protein (BMP) and TGF-β/Activin subfamilies that predominantly signal through discrete signaling pathways composed of heterotetrameric receptors and Smad signal transducers. Many of the ligands have context-dependent and/or concentration-dependent functions. BMPs are best known for their roles in development, but evidence is emerging for their roles as regulators of homeostasis. While the core components of TGF-β signaling pathways have been identified for more than 25 years, how these pathways produce context-dependent outcomes remains poorly understood. In the nematode Caenorhabditis elegans, there are only five TGF-β ligands, two type I receptors, and one type II receptor, providing an opportunity to dissect ligand-ligand and ligand-receptor interactions in a smaller number of combinations than in vertebrates. Our preliminary data have established that DBL-1/BMP functions in lipid metabolism and in innate immunity through mechanisms that are distinct from its roles in development. Furthermore, we identified a role for TIG-2 (BMP-like) and TIG-3 (TGF-β/Activin-like) in the immune response that may be mediated by the BMP-responsive Smad SMA-3. We are therefore poised to exploit this system to identify context-dependent mechanisms that distinguish these physiological outcomes from the developmental functions of signaling. Our research goals are to address these unanswered questions: (1) What are the determinants of signaling specificity for TGF-β-related signaling pathways? Hypothesis: Alternative ligand-ligand and ligand-receptor interactions are a mechanism for context-dependent responses. (2) How does BMP signaling execute its fat-regulatory function at the subcellular and molecular levels? Hypothesis: Genetic suppressors of the low-fat phenotype of dbl-1 mutants will reveal regulatory networks that interact with BMP signaling to modulate fat storage. (3) Does altered lipid metabolism impact resilience to pathogen exposure? Hypothesis: BMP-dependent mobilization of lipid stores contributes to survival on pathogenic bacteria. Our established assays for fat accumulation and pathogen survival provide whole- organism functional assessments for signaling. We will employ classical genetics, imaging, genomics, and biochemistry to test our hypotheses at a mechanistic level. This integration of approaches, combined with the reduced quantitative complexity in TGF-β signaling components, makes C. elegans the ideal model to address these gaps in knowledge. Due to the high degree of conservation of TGF-β signaling pathways, we anticipate valuable insight into universal mechanistic principles with implications for human health and disease.