EGFR-dependent TOR-independent endocycles support Drosophila gut epithelial regeneration

• Published in: Nature communications Vol. 8; no. 1; p. 15125
• Main Authors: Xiang, Jinyi, Bandura, Jennifer, Zhang, Peng, Jin, Yinhua, Reuter, Hanna, Edgar, Bruce A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09-05-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/51; 14/19; 38; 38/88; 38/89; 38/90; 38/91; 631/136/83/2359; 631/80/86/2367; 631/80/86/2368; 64/24; 96/109; 96/21; 96/34; 96/63; 96/95; Adaptation; Animals; Cell cycle; Cell Differentiation; Cell growth; Cell Proliferation; Clone Cells; Cyclin-dependent kinases; Drosophila melanogaster - metabolism; Drosophila Proteins - metabolism; Endoreduplication; Enterocytes - metabolism; Enterocytes - pathology; Epidermal growth factor; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelium - physiology; Genetic testing; Homeostasis; Humanities and Social Sciences; Insects; Intestines - cytology; Kinases; Mitogen-Activated Protein Kinases - metabolism; Models, Biological; multidisciplinary; Physiology; Ploidies; ras Proteins - metabolism; Receptor, Epidermal Growth Factor - metabolism; Receptors, Invertebrate Peptide - metabolism; Regeneration; Science; Science (multidisciplinary); Signal Transduction; Stem cells; TOR Serine-Threonine Kinases - metabolism; Transcription factors; Transcription, Genetic; Up-Regulation - genetics; Germany
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms15125

Following gut epithelial damage, epidermal growth factor receptor/mitogen-activated protein kinase (EGFR/MAPK) signalling triggers
Drosophila
intestinal stem cells to produce enteroblasts (EBs) and enterocytes (ECs) that regenerate the gut. As EBs differentiate into ECs, they become postmitotic, but undergo extensive growth and DNA endoreplication. Here we report that EGFR/RAS/MAPK signalling is required and sufficient to drive damage-induced EB/EC growth. Endoreplication occurs exclusively in EBs and newborn ECs that inherit EGFR and active MAPK from fast-dividing progenitors. Mature ECs lack EGF receptors and are refractory to growth signalling. Genetic tests indicated that stress-dependent EGFR/MAPK promotes gut regeneration via a novel mechanism that operates independently of Insulin/Pi3K/TOR signalling, which is nevertheless required in nonstressed conditions. The
E2f1
transcription factor is required for and sufficient to drive EC endoreplication, and Ras/Raf signalling upregulates
E2f1
levels posttranscriptionally. We illustrate how distinct signalling mechanisms direct stress-dependent versus homeostatic regeneration, and highlight the importance of postmitotic cell growth in gut epithelial repair.
In response to gut epithelial damage,
Drosophila
stem cells proliferate to produce large polyploid enterocytes (EC), which comprise the bulk of the epithelium. Here, the authors show that stress-dependent EGFR/MAP kinase signalling drives both endoreplication and cell growth in newborn ECs.