Identification of hormones regulating the C. elegans molting cycle
Final Report Abstract
Nematodes, like the model organism C. elegans, develop through several larval stages, each followed by a genetically encoded molting program during which a new cuticle is synthesized and the old one is shed. Understanding the regulatory mechanisms of this molting program can lead to discovery of novel paradigms of developmental control as well as possible ways to control parasitic nematodes that impact humans, live stock and agriculture. Previous research suggests that hormone-regulated transcription factors, called hormone receptors (NRs), and their corresponding hormones play key roles in regulating this developmental program. However, no regulatory, direct gene-to-gene interaction or any hormones have been described in detail so far to support this hypothesis. The proposed project aimed at identifying molt-regulating hormones present in the C. elegans metabolome by developing assays to detect bio-activity of the proposed molting hormones. Subsequently, the structure of active compounds will be elucidated, de novo synthesized and validated by in vitro and in vivo activity testing. To develop hormone activity assays as the fundamental tool for hormone discovery and validation, a gene was identified that is a strong candidate for being a direct regulatory target of two molt-regulating hormone receptors. The work done during the Foerderungszeitraum showed that characteristics intrinsic to the involved NRs prevent the development of assays similar to those successfully used for previous NR ligand identification. After the end of the Foerderungszeitraum, a novel, unbiased, high content and high throughput compatible screening pipeline was developed. The validation of this novel assay is still to come.
Publications
- "Interaction of structure-specific and promiscuous G-protein-coupled receptors mediates small-molecule signaling in Caenorhabditis elegans." Proc Natl Acad Sci USA. 2012 Jun 19;109(25):9917-22
Park D, O ' Doherty I, Somvanshi RK, Bethke A, Schroeder FC, Kumar U, Riddle DL
- "Comparative metabolomics reveals endogenous ligands of DAF-12, a nuclear hormone receptor, regulating C. elegans development and lifespan." Cell Metab. 2014 Jan 7;19(1):73-83
Mahanti P, Bose N, Bethke A, Judkins JC, Wollam J, Dumas KJ, Zimmerman AM, Campbell SL, Hu PJ, Antebi A, Schroeder FC
(See online at https://doi.org/10.1016/j.cmet.2013.11.024)
