MicroRNA pathways and stress resistance in C. elegans

2012 senior Scholar Award in aging

Animals are tough. Their developmental processes and physiological regulatory mechanisms are astonishingly robust despite the slings and arrows of environmental contingencies, including changing temperature, food availability, and pathogen infection. The nematode C. elegans exemplifies this remarkable robustness in surviving the harsh and changeable conditions of its normal habitat, which in the case of this worm is soil and decaying organic matter. Indeed, developing worm larvae and reproductive adults successfully cope with wide swings in temperature and fluctuations in the quantity, quality, and toxicity of their food, which consists of primarily bacteria. Amazingly, the pattern of cell divisions and differentiation of C. elegans development (referred to as the worm’s “invariant cell lineage”) occurs with exquisitely reproducible precision despite a broad range of potential stresses and environmental changes that the animal can experience.

Genetic and molecular studies have uncovered mechanisms by which gene expression is orchestrated to control, on the one hand, cellular growth and differentiation during development of animals, and, on the other hand, how animals sense and respond to environmental stresses. The essential properties of environmental response pathways include, i) detecting salient properties of the external or internal environment, ii) transducing environmental information through cellular signaling pathways, and iii) eliciting adaptive changes in gene activity. For many of these pathways the core molecular and genetic machinery are conserved between nematodes and mammals.

This project will use the C. elegans model to explore mechanisms of gene regulation in response to environmental change, with an emphasis on the roles of microRNAs in buffering developmental mechanisms against stress. MicroRNAs are versatile posttranscriptional regulators of genes and genetic networks. Therefore microRNAs can act at regulatory nodes that coordinate the activities of diverse physiological and developmental mechanisms, and potentially can buffer parts of the network from perturbations of other parts. In this fashion, microRNAs can enable the animal to survive changing and adverse environmental conditions. In our studies, we will focus on two classes of environmental stresses that are arguably the dominant factors in a worm's interactions with its environment: temperature and bacterial food source. The food source context relates to how the animal responds physiologically to bacterial diets with varying nutritional content and varying pathogenic potential. The temperature shift context relates to how the animal manages to develop normally despite wide variation in cellular thermodynamics.

We believe that this project should uncover mechanisms and principles that are fundamental to the biology of all animals. If successful, the proposed research will lead to a better understanding of how cells and tissues adapt to the animal's internal and external environment, and how those adaptive responses are integrated with developmental and homeostatic mechanisms to promote robust cell fate specification, morphogenesis, and tissue integrity.

Victor Ambros Ph.D.
University of Massachusetts Medical School