Cytokine and microbiota function in gut development: spatiotemporal analysis in the zebrafish

ongoing

Organ development and function are controlled by complex interactions between genetic, cellular, and environmental factors. Because these interactions are challenging to study in live organisms, their mechanisms remain largely unknown. Gut development is regulated by microbiota colonization, making it a valuable organ for dissecting gene-environment interactions. Cytokines, small secreted proteins highly responsive to environmental changes, regulate immunity and gut function in mammals. Our data indicate that specific cytokines are also essential for gut development in zebrafish. We found that these cytokines are first expressed in gut epithelial cells during development, and later their expression is switched to immune cells, including innate lymphoid cells (ILCs). ILCs were discovered in the mammalian gut but their function has not been dissected due to the lack of specific markers. Having identified the first vertebrate ILC markers in zebrafish, we will combine our novel tools together with other unique benefits of zebrafish such as live microscopy, easy environmental manipulation and abundant genetic tools, to dissect how microbial cues interact with genetic networks to control organ development. We hypothesize that gut development is regulated by cytokine signaling that is, in turn, regulated by crosstalk with the microbiota, and the emergence of ILCs. Our specific aims are to: 1. Characterize the roles of cytokines during gut development 2. Determine how microbiota-cytokine crosstalk controls gut development 3. Uncover the role of ILCs and cytokine source switching in gut maturation This project, at the intersection of developmental biology and immunology, will provide fundamental insights into how symbiont-host crosstalk controls organogenesis, and a new conceptual framework for the function of the immune system. Furthermore, conservation with the human gut could help identify new therapeutic strategies for common diseases such as inflammatory bowel disease