Integration of BMP and Insulin/IGF-1 Signaling Regulates Multiple Homeostatic Functions in \u3ci\u3eCaenorhabditis elegans\u3c/i\u3e

Abstract

The maintenance of homeostatic functions is key to the survival and well-being of an organism. Regulation of homeostasis relies on varied inputs, both intrinsic and extrinsic, to potentiate a web of interconnected signaling relays. Insulin/IGF-1 signaling (IIS) is a well-known regulator of glucose and lipid metabolism, as well as having far reaching effects in other homeostatic mechanisms. On the other hand, bone morphogenetic protein (BMP), a member of the transforming growth factor beta signaling superfamily, is known for its role in differentiation and development, with only recent studies highlighting potential roles in metabolic homeostasis. Here we elucidate new functions for C. elegans DBL-1/BMP signaling in regulating homeostasis through interaction with DAF-2/IIS via three distinct patterns of interaction. First, we show that both pathways can work independently, as seen in the regulation of body size. Second, we show that the two pathways can work via an epistatic relationship; DBL-1/BMP functions upstream of DAF-2/IIS to influence intestinal lipid stores through the regulation of ins-4. Lastly, we identify an antagonistic mode of interaction where DBL-1/BMP can interact with DAF-2/IIS downstream of daf-2/InsR through changes in the localization of SKN-1. Together, these data highlight various means by which both DBL-1/BMP and DAF-2/IIS can co-regulate homeostatic functions in C. elegans. The complexity and redundancy found in many mammalian pathways proves a difficult hurdle in elucidating mechanisms of interaction. Here we provide a model to further study the interactions of BMP and IIS to provide insight into human homeostasis