Division of Labor: Roles of Groucho and CtBP in Notch-Mediated Lateral Inhibition that Controls Intestinal Stem Cell Differentiation in Drosophila

• Published in: Stem cell reports 2019-05, Vol.12 (5), p.1007-1023
• Main Authors: Guo, Xingting, Huang, Huanwei, Yang, Ziqing, Cai, Tao, Xi, Rongwen
• Format: Article
• Language: English
• Subjects: Alcohol Oxidoreductases - genetics; Alcohol Oxidoreductases - metabolism; Animals; Animals, Genetically Modified; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cell Differentiation - genetics; Cell Division - genetics; Cell Proliferation - genetics; CtBP; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Drosophila; Drosophila melanogaster - cytology; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; E(spl)-C; enteroblast; Gene Expression Regulation, Developmental; Groucho; intestinal stem cell; Intestines - cytology; lateral inhibition; Notch; Receptors, Notch - genetics; Receptors, Notch - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA Interference; Signal Transduction - genetics; Stem Cells - cytology; Stem Cells - metabolism
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2019.03.005

Intestinal stem cell (ISC) differentiation in the Drosophila midgut requires Delta/Notch-mediated lateral inhibition, which separates the fate of ISCs from differentiating enteroblasts (EBs). Although a canonical Notch signaling cascade is involved in the lateral inhibition, its regulation at the transcriptional level is still unclear. Here we show that the establishment of lateral inhibition between ISC-EB requires two evolutionarily conserved transcriptional co-repressors Groucho (Gro) and C-terminal binding protein (CtBP) that act differently. Gro functions in EBs with E(spl)-C proteins to suppress Delta expression, inhibit cell-cycle re-entry, and promote cell differentiation, whereas CtBP functions specifically in ISCs to mediate transcriptional repression of Su(H) targets and maintain ISC fate. Interestingly, several E(spl)-C genes are also expressed in ISCs that cooperate with Gro to inhibit cell proliferation. Collectively, our study demonstrates separable and cell-type-specific functions of Gro and CtBP in a lateral inhibition process that controls the proliferation and differentiation of tissue stem cells. [Display omitted] •Gro and CtBP are required for lateral inhibition between ISC and EB in fly midgut•Gro cooperates with E(spl)-C factors in EBs to promote differentiation•CtBP cooperates with Hairless in ISCs to maintain stem cell fate•Gro and E(spl)-C mediate baseline Notch activity and thereby restrict ISC division In this article, Rongwen Xi and colleagues show that the establishment of lateral inhibition between ISCs and EBs in the Drosophila midgut requires Gro and CtBP that act differently. Gro functions in EBs with E(spl)-C proteins to suppress Delta expression and inhibit cell-cycle re-entry, whereas CtBP functions specifically in ISCs to mediate transcriptional repression of Su(H) targets and maintain ISC fate.