Growth, blunting and regeneration of C. elegans intestinal microvilli – GroBluRe

The apical membrane of the intestinal epithelium presents a network of actin-based microvilli essential for food absorption. Intestinal microvilli blunting can be inherited as in Microvillus Inclusion Disease, or acquired due to inflammatory diseases, toxins or pathogens, and is often associated with a severe morbidity. Meanwhile, microvilli regeneration has been observed in a few instances but never characterized, thus providing the opportunity to investigate a rare case of biological regeneration at the subcellular level in a potential therapeutic perspective.
We propose to molecularly characterize microvilli growth, blunting and regeneration in a living organism. We recently described the growth and dynamics of microvilli during development in C. elegans. We also established several models mimicking inherited and acquired disorders leading to microvillus blunting in C. elegans. In the first task, we will first use a proteomic approach to systematically identify new microvilli components; we will then characterize the role of all major microvilli factors during brush border formation through loss of function studies; this will lead to an in-depth characterization of microvilli growth and maintenance during C. elegans embryonic and post-embryonic development. In the second task, we will next characterize microvilli blunting using several inherited and acquired models, as well as microvilli lengthening linked to natural C. elegans microbiome isolates. This task will lead to the first in vivo characterization of microvilli blunting in several pathological or physiologically relevant backgrounds. Finally, in the third task, we will investigate for the first time in vivo microvilli regeneration, by identifying factors implicated in this process, characterizing their function, and examining a potential role of the intestinal microbiome.
Altogether this project will investigate a little-studied subcellular regenerative process which could open the way to identify new therapeutic options to treat microvilli blunting