The function of the SMG-8 protein during Caenorhabditis elegans embryogenesis

The main goal of my project is to unravel the function of SMG-8, a protein that is highly conserved across the animal kingdom yet its function is unknown. SMG-8 is of particular interest since it is of the few known FoxA/PHA-4 regulators during Caenorhabditis elegans development. FoxA/PHA-4 is the master regulator of foregut development and FoxA/PHA-4 mutants do not form a pharynx and die at the end of embryogenesis. The key to understanding the role of smg-8 is to analyze its activity in vivo using smg-8 mutants. The nematode C. elegans offers the only known smg-8 mutants and the only known loss-of-function phenotype, which makes worms the ideal model organism to investigate the role of SMG-8 in vivo. The specific goals of my project are: 1) SMG-8 was identified during a screen as a suppressor of FoxA/pha-4. The underlying mechanism of how SMG-8 modulates FoxA/PHA-4 is completely unknown. I will determine if SMG-8 targets FoxA/PHA-4 protein or mRNA and will map sequences within pha-4 that are SMG-8 responsive. I will use what I learn about pha-4 and perform a screen to identify additional SMG-8 targets. 2) In the original screen that uncovered smg-8, additional FoxA/PHA-4 suppressors were found, some of which may function in the smg-8 pathway. I will survey the FoxA/PHA-4 suppressors for those with genetic characteristics that make them good candidates to be in the SMG-8 pathway. This genetic analysis will also set the stage for future molecular studies. SMG-9 - one of only few putative SMG-8 binding partners - offers the ideal entry point to begin and extend the SMG-8 pathway. I will begin by exploring the interactions between SMG-8 and SMG-9, characterize their binding and test if both proteins target the same region of the pha-4 gene. These goals will help illuminate the role of SMG-8 during embryogenesis and expand the pathway. They will also shed like on human disease, since preliminary data suggest a role in cancer. Consequently, understanding the SMG-8 function could promote the development of new cancer treatments or prognostics. The conservation of SMG-8 and its interactions across the animal kingdom will enable researchers to transfer knowledge gained in C. elegans into mammalian systems and cancer biology.

DFG Programme Research Fellowships

International Connection USA

Host Professorin Dr. Susan Elizabeth Mango