Identification and Synthesis of Small Molecules in Caenorhabditis Elegans

Abstract

Due to its high homology to higher animals, Caenorhabditis elegans has become one of the most important model organisms for human biology. It has become the model of choice for studying development, aging, and diabetes. Whereas C. elegans genetics and physiology have been studied extensively, its metabolome has remained largely uncharacterized. However, recent studies indicate that yet unidentified small molecules may be involved in regulating almost every aspect of C elegans’ life history.This dissertation presents contributions to the collective knowledge of small molecules that are associated with organismal development and sex. We began our investigations with a comprehensive comparison of the metabolome of male nematodes, which are present as a small minority in a population of C. elegans and, with that of the dominant sex, the hermaphrodites. Next, through the use of mutant animals, we investigated which male-specific compounds are derived from the male germline and which compounds are derived from the male soma, and how production of these compounds is tied to development and aging. One of the compounds we identified was nacq#1, which increases the rate of sexual development and reproduction in hermaphrodites at the expense of a shortened lifespan. In addition to nacq#1, we found five additional classes of compounds, as well as other individual small molecules, that are enriched in or specific to males. In addition, we contributed new chemical tools to investigate the biology of a known class of molecules called dafachronic acids (dafa#s) which are responsible for continued development of C. elegans. Through isotopic labeling we probed the metabolism of known dafachronic acids to find potentially more active ligands as well as degradation products.