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

• Applicant: Dr. Antje Fischer
• Subject Area: Developmental Biology ; Evolutionary Cell and Developmental Biology (Zoology)
• Term: Funded in 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 261591459

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 Mango