The WT1-like transcription factor Klumpfuss maintains lineage commitment of enterocyte progenitors in the Drosophila intestine

• Published in: Nature communications Vol. 10; no. 1; pp. 4123 - 13
• Main Authors: Korzelius, Jerome, Azami, Sina, Ronnen-Oron, Tal, Koch, Philipp, Baldauf, Maik, Meier, Elke, Rodriguez-Fernandez, Imilce A., Groth, Marco, Sousa-Victor, Pedro, Jasper, Heinrich
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.09.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 14/19; 38/91; 45/100; 45/88; 631/136; 631/136/532/1360; 631/136/532/2437; 64/24; 96/1; 96/44; Absorptivity; Animals; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell Differentiation; Cell fate; Cell Lineage; Cell Proliferation; Differentiation (biology); DNA-Binding Proteins - metabolism; Drosophila; Drosophila melanogaster - cytology; Drosophila Proteins - metabolism; Enterocytes - cytology; Homeostasis; Humanities and Social Sciences; Initial specifications; Insects; Intestines - cytology; Midgut; Models, Biological; multidisciplinary; Progenitor cells; Protein Binding; Receptors, Notch - metabolism; Science; Science (multidisciplinary); Signal Transduction; Small intestine; Stem cells; Stem Cells - cytology; Stem Cells - metabolism; Transcription factors; Transcription Factors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-12003-0

In adult epithelial stem cell lineages, the precise differentiation of daughter cells is critical to maintain tissue homeostasis. Notch signaling controls the choice between absorptive and entero-endocrine cell differentiation in both the mammalian small intestine and the Drosophila midgut, yet how Notch promotes lineage restriction remains unclear. Here, we describe a role for the transcription factor Klumpfuss (Klu) in restricting the fate of enteroblasts (EBs) in the Drosophila intestine. Klu is induced in Notch-positive EBs and its activity restricts cell fate towards the enterocyte (EC) lineage. Transcriptomics and DamID profiling show that Klu suppresses enteroendocrine (EE) fate by repressing the action of the proneural gene Scute, which is essential for EE differentiation. Loss of Klu results in differentiation of EBs into EE cells. Our findings provide mechanistic insight into how lineage commitment in progenitor cell differentiation can be ensured downstream of initial specification cues. Notch signaling mediates intestinal enteroblast specification in Drosophila but the molecular mechanism as to how this is regulated is unclear. Here, the authors show that the transcription factor Klumpfuss ensures enteroblast commitment through repression of enteroendocrine cell fate downstream of Notch.