Project Summary
The Transforming Growth Factor beta (TGF-ß) family of secreted peptide growth factors plays significant roles
in cell function, tissue patterning, and organismal homeostasis. Dysregulation of TGF-ß 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-ß/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-ß 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-ß 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-ß/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-ß-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-ß signaling components, makes C. elegans the ideal model to address
these gaps in knowledge. Due to the high degree of conservation of TGF-ß signaling pathways, we anticipate
valuable insight into universal mechanistic principles with implications for human health and disease.