Deciphering the role of thyrostimulin signaling in C. elegans

Glycoprotein hormones (GPHs), such as chorionic gonadotropin, luteinizing hormone, follicle stimulating hormone, and thyroid stimulating hormone, are key regulators of animal physiology and homeostasis. Each GPH is made up of two subunits, a hormone-specific β-subunit and a “common” shared α-subunit. In 2002, Nakabayashi et al. discovered a fifth GPH in the human anterior pituitary gland, called thyrostimulin. This hormone does not share an α-subunit with the other GPHs. Instead, it has a hormone-specific α- and β-subunit (GPA2 and GPB5). Gene orthologues have been identified in both vertebrates and invertebrates, suggesting that GPA2 and GPB5 are ancestral glycoprotein genes from which other subunits may have diverged. Orthologues of GPA2 and GPB5 are also found in the nematode model organism Caenorhabditis elegans. Our research group previously discovered that, similar to human thyrostimulin, thyrostimulin in C. elegans activates thyroid stimulating hormone (TSH)-like receptors in vitro. Thyrostimulin also appears to play a role in the regulation of growth in C. elegans. Other work (see Oishi et al., 2009) also indicates that thyrostimulin receptor signaling may regulate protective innate immune responses. The exact signaling mechanisms and possible roles of thyrostimulin in these responses have not yet been determined. This project aims to further identify the possible function(s) and signaling pathway(s) that thyrostimulin governs within the context of C. elegans growth, immunity, and intestinal function. C. elegans is a powerful model for dissecting the functions of this key regulatory system due to the strong structural and functional conservation of the thyrostimulin signaling system and its existing array of genetic tools and functional assays for testing phenotypes. We expect our findings to shed light on the physiological roles of this neuroendocrine system and its evolution.