Deciphering the role of entero-endocrine differentiation in intestinal homeostasis

• Applicant: Dr. Jerome Korzelius, Ph.D.
• Subject Area: Developmental Biology ; General Genetics and Functional Genome Biology
• Term: from 2017 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 383760161

The intestine is not only an organ that is important for providing the body with nutrients, it also acts as an endocrine signaling center that couples nutritional information to organismal metabolism and feeding behaviour. The entero-endocrine (EE) cells in the intestine mediate these processes through the production of various hormones. Despite their importance, not much is known about how EE cells are formed from their tissue-specific stem cells and the influence EE cells exert on the microbiome, organismal aging and stress responses. In this project, we will use the Drosophila intestine to study EE differentiation and the role of EEs in intestinal homeostasis. Highly analogous to the mammalian intestine, the Drosophila intestine is maintained by a population of intestinal stem cells (ISCs) that replace damaged cells to maintain organ homeostasis during life. ISC function declines during aging, leading to dysbiosis of the microbiome, highly induced cellular stress pathways and eventual organ failure. Our previous work has shown that the transcription factor escargot (Esg) plays a central role in maintaining the undifferentiated state of ISCs by repressing differentiation factors in the stem-progenitor compartment. By performing cell-type specific transcriptomics, we identified the transcription transcription factor klumpfuss (Klu) as a likely regulator of differentiation in the intestine. Our preliminary data show that loss of Klu leads to the formation of excess EE cells in the intestine. Conversely, ectopic expression of Klu in the Drosophila intestinal stem cells (ISCs) leads to a block in EE differentiation. This proposal will identify the mechanism of Klu action in EE differentiation and the role of EE cells in age-related dysbiosis using a combination of genetics, transcriptomics and transcription-factor binding studies. Aim 1 of the project will identify the genetic interactions of Klu with known regulators of EE differentiation by using state of the art Drosophila genetics. Under Aim 2, we will use cell-specific transcriptome profiling and DNA-binding studies of Klu to identify critical downstream targets of Klu that clarify the mechanism by which Klu regulates EE differentiation. In Aim 3, we will use manipulation of Klu to manipulate the number of EE cells in the intestine to address the general role of EE cells in attenuating age-related dysbiosis and ISC functional decline during aging. This proposal will advance our knowledge on entero-endocrine differentiation and the importance of EE cells on organ homeostasis during life.

• DFG Programme: Research Grants