The gastrointestinal tract contains the largest population of hormone-producing cells in the body. These enteroendocrine cells, scattered throughout the digestive epithelium, secrete over fifteen different hormones, regulating important physiological functions such as glycaemia, pancreatic secretion and food intake. Understanding enteroendocrine cell differentiation is essential for identifying future targets for common disease such as diabetes and obesity.
To get a comprehensive view of the formation of these cells, we determined the transcriptomic landscape of enteroendocrine cells through RNAseq analyses of 4 dpf FACS sorted pax6b:GFP enteroendocrine cells. We found that the vast majority of the hormones described to be expressed in the gastrointestinal tract of the mouse are also expressed in the zebrafish gut. This transcriptomic analysis also highlighted the expression in the gut of four hormones not yet reported to be expressed in enteroendocrine cells of any species. Furthermore, we noticed a high similarity between enteroendocrine and pancreatic endocrine cells as many transcription factors expressed in the pancreas are also expressed in the gut. Among them, the LIM transcription factor Isl1 labels only a subset of enteroendocrine cells. The null isl1sa0029 mutant displays a drastic and specific reduction of the expression of the hormones synthetized by the corresponding enteroendocrine cell types. In contrast, the expression of transcription factors, thought to be important for the formation of the enteroendocrine progenitor cells, like ascl1a, sox4b and neurod1, is not perturbed in the isl1sa0029 mutant. The transcriptomic comparison by RNAseq of wt and mutant isl1sa0029 embryos identified 530 differentially expressed genes and among them, only a very limited number of transcription factors. Altogether, this suggests that Isl1 controls the last steps of the differentiation process of specific enteroendocrine cells.