The long term goal of this work is to define how microRNAs fit into complex developmental and physiological networks. The identification of pathways and targets regulated by individual microRNAs is vital to understand microRNA function in animal development and in human disease. As an eminently genetically-tractable animal, C. elegans provides an ideal model system in which to study the functions of microRNAs, particularly as many microRNAs show complete or near-complete conservation between worms and humans. The proposed research is focused on the single biological process of ovulation. Ovulation is a calcium-dependent rhythmic behavior that requires microRNAs. The central questions of this work are: 1) what specific events of ovulation require microRNAs? 2) What individual microRNAs function in the germ cells or somatic gonad to regulate ovulation and 3) what pathways and direct targets are regulated by these microRNAs? To address these questions we will use genetic approaches to conditionally reduce microRNA biogenesis activity to determine specific ovulation events that require microRNAs. In addition, we will use high-throughput sequencing to profile microRNAs that are expressed in the somatic gonad. Lastly, we will identify which somatic gonad microRNAs contribute to the control of ovulation and determine the pathways and targets that they regulate. This comprehensive analysis of a single biological process provides an opportunity to define how microRNA's act in complex regulatory networks.
The work in this proposal will focus on miRNAs conserved between worms and mammals. Achieving the goals of this project will provide key information about pathways regulated by miRNAs during development that may be misregulated in human disease and to further describe the biological principles of miRNA regulation of target mRNAs in animals. PUBLIC HEALTH RELEVANCE: MicroRNAs are indispensable regulators of gene expression that are required for animal development and physiology. In addition, microRNAs have been implicated in a wide spectrum of human diseases, notably cardiovascular disease, neurodegenerative disease, diabetes, and cancer. We are using the genetically-tractable organism, C. elegans, to identify the pathways and targets that are regulated by microRNAs. This will further our understanding of the function of microRNAs in animal development and in human disease.
|Kemp, Benedict J; Allman, Erik; Immerman, Lois et al. (2012) miR-786 regulation of a fatty-acid elongase contributes to rhythmic calcium-wave initiation in C. elegans. Curr Biol 22:2213-20|
|Brenner, John L; Kemp, Benedict J; Abbott, Allison L (2012) The mir-51 family of microRNAs functions in diverse regulatory pathways in Caenorhabditis elegans. PLoS One 7:e37185|
|Abbott, Allison L (2011) Uncovering new functions for microRNAs in Caenorhabditis elegans. Curr Biol 21:R668-71|
|Brenner, John L; Jasiewicz, Kristen L; Fahley, Alisha F et al. (2010) Loss of individual microRNAs causes mutant phenotypes in sensitized genetic backgrounds in C. elegans. Curr Biol 20:1321-5|