1. The transcriptional corepressor MTGR1 regulates intestinal secretory lineage allocation.
- Author
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Parang B, Rosenblatt D, Williams AD, Washington MK, Revetta F, Short SP, Reddy VK, Hunt A, Shroyer NF, Engel ME, Hiebert SW, and Williams CS
- Subjects
- Animals, Apoptosis drug effects, Blotting, Western, Cell Differentiation drug effects, Cell Proliferation drug effects, Cells, Cultured, Epithelial Cells drug effects, Epithelial Cells metabolism, Flow Cytometry, Immunoenzyme Techniques, Immunoprecipitation, Intestinal Mucosa metabolism, Intestines drug effects, Mice, Mice, Knockout, Paneth Cells cytology, Paneth Cells drug effects, Paneth Cells metabolism, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Receptors, Notch genetics, Reverse Transcriptase Polymerase Chain Reaction, Amyloid Precursor Protein Secretases antagonists & inhibitors, Cell Lineage, Epithelial Cells cytology, Intestines cytology, Protease Inhibitors pharmacology, Receptors, Notch metabolism, Repressor Proteins physiology
- Abstract
Notch signaling largely determines intestinal epithelial cell fate. High Notch activity drives progenitors toward absorptive enterocytes by repressing secretory differentiation programs, whereas low Notch permits secretory cell assignment. Myeloid translocation gene-related 1 (MTGR1) is a transcriptional corepressor in the myeloid translocation gene/Eight-Twenty-One family. Given that Mtgr1(-/-) mice have a dramatic reduction of intestinal epithelial secretory cells, we hypothesized that MTGR1 is a key repressor of Notch signaling. In support of this, transcriptome analysis of laser capture microdissected Mtgr1(-/-) intestinal crypts revealed Notch activation, and secretory markers Mucin2, Chromogranin A, and Growth factor-independent 1 (Gfi1) were down-regulated in Mtgr1(-/-) whole intestines and Mtgr1(-/-) enteroids. We demonstrate that MTGR1 is in a complex with Suppressor of Hairless Homolog, a key Notch effector, and represses Notch-induced Hairy/Enhancer of Split 1 activity. Moreover, pharmacologic Notch inhibition using a γ-secretase inhibitor (GSI) rescued the hyperproliferative baseline phenotype in the Mtgr1(-/-) intestine and increased production of goblet and enteroendocrine lineages in Mtgr1(-/-) mice. GSI increased Paneth cell production in wild-type mice but failed to do so in Mtgr1(-/-) mice. We determined that MTGR1 can interact with GFI1, a transcriptional corepressor required for Paneth cell differentiation, and repress GFI1 targets. Overall, the data suggest that MTGR1, a transcriptional corepressor well characterized in hematopoiesis, plays a critical role in intestinal lineage allocation., (© FASEB.)
- Published
- 2015
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