Deciphering the role of entero-endocrine differentiation in intestinal homeostasis
General Genetics and Functional Genome Biology
Final Report Abstract
The intestine is a key tissue in the physiology of many metazoans and is the primary tissue for the digestion and metabolism of our food. It is also a key contact point for exposure to pathogens and the intestine is constantly exposed to a variety of pathogens. Furthermore, the high metabolic activity of this tissue causes a vast amount of wear and tear for the cells performing nutrient uptake and breakdown. To replace all the dead and dying cells in the intestine, our gut and that of many other animals depends on specialized adult stem cells called Intestinal Stem Cells (ISCs), that actively replenish cells in the intestine. These cells can divide indefinitely and replace specialized (differentiated) intestinal cells such as the enterocytes (EC) that take up nutrients and entero-endocrine cells (EE) that produce hormones that send signals to distant parts of the body, such as the liver or brain. Both the division and the differentiation of these ISCs is tightly controlled by various signalling pathways and proteins called transcription factors (TFs) that turn the expression of specific genes on and off. If these signals go awry, this can lead to the development of benign tumours called adenomas that can subsequently develop into malignant carcinomas. In fact, colorectal cancer (CRC) is one of the top 3 most prevalent tumours and still has a poor 5-year survival rate. To better understand the differentiation of ISCs, we used the fruit fly (Drosophila melanogaster) intestine as model. The fly intestine offers a simple paradigm for the study of adult stem cell differentiation: ISCs divide and their daughters either differentiate into large absorptive enterocytes (ECs), or into small secretory enteroendocrine cells (EEs). EEs are small and make up less than 5% of the intestine (~1% in mammals) but form the largest endocrine hub of the animal. They produce a variety of peptide hormones that influence a wide variety of organismal responses, such as food intake, peristalsis, gastric emptying as well as mood and activity. In this project, we studied the role of the TF Klumpfuss (Klu) in EE differentiation. We found that Klu is a Notch target gene that is exclusively active in EC-precursor cells, where it represses key genes involved in EE differentiation. Loss of Klu leads to excess EE differentiation in the gut, and analysis of Klu-binding of target genes identified the EE inducing TF Scute as a key downstream target. In addition, the analysis of Klu target genes identified both known and novel genes involved in EE differentiation and ISC function. One of these genes, a TF called Chronophage (Cph), was found to increase expression with age and in tumors and plays a key role in ISC proliferation as well as EE differentiation. In summary, this project has resulted in an increased understanding of EE differentiation and key changes in EE signalling with age. With lifespan increasing globally, understanding age-related changes in EE differentiation becomes increasingly important.
Publications
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The WT1-like transcription factor Klumpfuss maintains lineage commitment of enterocyte progenitors in the Drosophila intestine. Nature Communications, 10(1).
Korzelius, Jerome; Azami, Sina; Ronnen-Oron, Tal; Koch, Philipp; Baldauf, Maik; Meier, Elke; Rodriguez-Fernandez, Imilce A.; Groth, Marco; Sousa-Victor, Pedro & Jasper, Heinrich
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Stem cell mTOR signaling directs region-specific cell fate decisions during intestinal nutrient adaptation. Science Advances, 10(6).
Mattila, Jaakko; Viitanen, Arto; Fabris, Gaia; Strutynska, Tetiana; Korzelius, Jerome & Hietakangas, Ville
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The transcription factor Chronophage/BCL11A/B promotes intestinal stem cell proliferation and endocrine differentiation. Cold Spring Harbor Laboratory.
King, Emer Aisling; Jacobsen, Eleanor; Woolner, Nicholas; de Navascués, Joaquín; Marshall, Owen J. & Korzelius, Jerome
