Zebrafish as a model for understanding enteric nervous system interactions in the developing intestinal tract

The enteric nervous system (ENS) forms intimate connections with many other intestinal cell types, including immune cells and bacterial consortia resident in the intestinal lumen. In this review, we highlight contributions of the zebrafish model to understanding interactions among these cells. Zebrafish is a powerful model for forward genetic screens, several of which have uncovered genes previously unknown to be important for ENS development. More recently, zebrafish has emerged as a model for testing functions of genes identified in human patients or large-scale human susceptibility screens. In several cases, zebrafish studies have revealed mechanisms connecting intestinal symptoms with other, seemingly unrelated disease phenotypes. Importantly, chemical library screens in zebrafish have provided startling new insights into potential effects of common drugs on ENS development. A key feature of the zebrafish model is the ability to rear large numbers of animals germ free or in association with only specific bacterial species. Studies utilizing these approaches have demonstrated the importance of bacterial signals for normal intestinal development. These types of studies also show how luminal bacteria and the immune system can contribute to inflammatory processes that can feedback to influence ENS development. The excellent optical properties of zebrafish embryos and larvae, coupled with the ease of generating genetically marked cells of both the host and its resident bacteria, allow visualization of multiple intestinal cell types in living larvae and should promote a more in-depth understanding of intestinal cell interactions, especially interactions between other intestinal cell types and the ENS.