MTGR1 is required to maintain small intestinal stem cell populations
Cell Death and Differentiation, vol. 31, pp. 1170–1183
Abstract
Abstract Undifferentiated intestinal stem cells (ISCs) are crucial for maintaining homeostasis and resolving injury. Lgr5 + cells in the crypt base constantly divide, pushing daughter cells upward along the crypt axis where they differentiate into specialized cell types. Coordinated execution of complex transcriptional programs is necessary to allow for the maintenance of undifferentiated stem cells while permitting differentiation of the wide array of intestinal cells necessary for homeostasis. Previously, members of the myeloid translocation gene (MTG) family have been identified as transcriptional co-repressors that regulate stem cell maintenance and differentiation programs in multiple organ systems, including the intestine. One MTG family member, myeloid translocation gene related 1 (MTGR1), has been recognized as a crucial regulator of secretory cell differentiation and response to injury. However, whether MTGR1 contributes to the function of ISCs has not yet been examined. Here, using Mtgr1 −/− mice, we have assessed the effects of MTGR1 loss specifically in ISC biology. Interestingly, loss of MTGR1 increased the total number of cells expressing Lgr5 , the canonical marker of cycling ISCs, suggesting higher overall stem cell numbers. However, expanded transcriptomic and functional analyses revealed deficiencies in Mtgr1 -null ISCs, including deregulated ISC-associated transcriptional programs. Ex vivo, intestinal organoids established from Mtgr1 -null mice were unable to survive and expand due to aberrant differentiation and loss of stem and proliferative cells. Together, these results indicate that the role of MTGR1 in intestinal differentiation is likely stem cell intrinsic and identify a novel role for MTGR1 in maintaining ISC function.
Authors 19
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University of Iowa · Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA
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Affiliation as printed
Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA
Vanderbilt University School of Medicine, Vanderbilt University, Nashville, TN, USA
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Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
Program in Chemical and Physical Biology, Vanderbilt University, Nashville, TN, USA
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Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA
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Affiliation as printed
Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
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VA Tennessee Valley Healthcare System · Vanderbilt University Medical Center
Affiliation as printed
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Veterans Affairs Tennessee Valley Health Care System, Nashville, TN, 37232, USA
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Vanderbilt University Medical Center
Affiliation as printed
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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The Ohio State University · Vanderbilt University Medical Center
Affiliation as printed
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
The Ohio State University College of Medicine, Columbus, OH, USA
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Vanderbilt University · Leiden University Medical Center · VA Tennessee Valley Healthcare System · Willem-Alexander Kinderziekenhuis · Vanderbilt University Medical Center
Affiliation as printed
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
Veterans Affairs Tennessee Valley Health Care System, Nashville, TN, 37232, USA
Willem-Alexander Children's Hospital, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
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Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
Department of Biostatistics, Vanderbilt University, Nashville, TN, USA
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Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
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Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
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Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
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Vanderbilt University · Weill Cornell Medicine
Affiliation as printed
Department of Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA
Vanderbilt University School of Medicine, Vanderbilt University, Nashville, TN, USA
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Vanderbilt University · VA Tennessee Valley Healthcare System · Vanderbilt University Medical Center
Affiliation as printed
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA
Veterans Affairs Tennessee Valley Health Care System, Nashville, TN, 37232, USA
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Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA
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Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
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Affiliation as printed
Department of Biochemistry, Vanderbilt University, Nashville, TN, USA
Vanderbilt University School of Medicine, Vanderbilt University, Nashville, TN, USA
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Christopher S. Williams corresponding
Vanderbilt University · VA Tennessee Valley Healthcare System · Vanderbilt University Medical Center
Affiliation as printed
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Christopher.williams@vanderbilt.edu
Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA. Christopher.williams@vanderbilt.edu
Vanderbilt University School of Medicine, Vanderbilt University, Nashville, TN, USA. Christopher.williams@vanderbilt.edu
Veterans Affairs Tennessee Valley Health Care System, Nashville, TN, 37232, USA. Christopher.williams@vanderbilt.edu
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