title: Msi RNA-binding proteins control reserve intestinal stem cell quiescence.
abstract: Regeneration of the intestinal epithelium is driven by multiple intestinal stem cell (ISC) types, including an active, radiosensitive WnthighISC that fuels turnover during homeostasis and a reserve, radioresistant Wntlow/offISC capable of generating active WnthighISCs. We examined the role of the Msi family of oncoproteins in the ISC compartment. We demonstrated that Msi proteins are dispensable for normal homeostasis and self-renewal of the active ISC, despite their being highly expressed in these cells. In contrast, Msi proteins are required specifically for activation of reserve ISCs, where Msi activity is both necessary and sufficient to drive exit from quiescence and entry into the cell cycle. Ablation of Msi activity in reserve ISCs rendered the epithelium unable to regenerate in response to injury that ablates the active stem cell compartment. These findings delineate a molecular mechanism governing reserve ISC quiescence and demonstrate a necessity for the activity of this rare stem cell population in intestinal regeneration.
authors: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.|Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104.
authors: Maryam
authors: M
authors: Yousefi
authors: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors: Ning
authors: N
authors: Li
authors: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors: Angela
authors: http://orcid.org/0000-0002-4631-7105
authors: A
authors: Nakauka-Ddamba
authors: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.|State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100083, China.
authors: Shan
authors: http://orcid.org/0000-0002-0429-8890
authors: S
authors: Wang
authors: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors: Kimberly
authors: http://orcid.org/0000-0003-0597-5475
authors: K
authors: Davidow
authors: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors: Jenna
authors: http://orcid.org/0000-0003-4278-669X
authors: J
authors: Schoenberger
authors: State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100083, China.
authors: Zhengquan
authors: http://orcid.org/0000-0001-8696-2013
authors: Z
authors: Yu
authors: Department of Biostatistics, the Wharton School, University of Pennsylvania, Philadelphia, PA 19104.
authors: Shane T
authors: ST
authors: Jensen
authors: Molecular Pharmacology and Chemistry Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors: Michael G
authors: http://orcid.org/0000-0002-1165-6991
authors: MG
authors: Kharas
authors: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104 lengner@vet.upenn.edu.|Department of Cell and Developmental Biology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.|Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104.|Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors: Christopher J
authors: http://orcid.org/0000-0002-0574-5189
authors: CJ
authors: Lengner
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D004848:Epithelium / Q000473:pathology / Q000528:radiation effects; D005720:Gamma Rays; D006706:Homeostasis / Q000528:radiation effects; D007422:Intestines / Q000166:cytology*; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D011832:Radiation Injuries / Q000473:pathology; D016192:Resting Phase, Cell Cycle / Q000528:radiation effects; D016196:S Phase / Q000528:radiation effects; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism* / Q000528:radiation effects; D015854:Up-Regulation / Q000528:radiation effects; D060449:Wnt Signaling Pathway / Q000528:radiation effects
chemical_list: C104786:Msi1h protein, mouse; C499059:Msi2h protein, mouse; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins