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Nature DOI:10.1038/nature11163

mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake.

Publication TypeJournal Article
Year of Publication2012
AuthorsYilmaz, ÖH, Katajisto, P, Lamming, DW, Gültekin, Y, Bauer-Rowe, KE, Sengupta, S, Birsoy, K, Dursun, A, V Yilmaz, O, Selig, M, G Nielsen, P, Mino-Kenudson, M, Zukerberg, LR, Bhan, AK, Deshpande, V, Sabatini, DM
Date Published2012 Jun 28
KeywordsADP-ribosyl Cyclase, Animals, Antigens, CD, Caloric Restriction, Cell Count, Cell Division, Cyclic ADP-Ribose, Energy Intake, Female, GPI-Linked Proteins, Intestines, Longevity, Male, Mice, Multiprotein Complexes, Paneth Cells, Paracrine Communication, Proteins, Regeneration, Signal Transduction, Sirolimus, Stem Cell Niche, Stem Cells, TOR Serine-Threonine Kinases

How adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here we find that Paneth cells, a key constituent of the mammalian intestinal stem-cell (ISC) niche, augment stem-cell function in response to calorie restriction. Calorie restriction acts by reducing mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells, and the ISC-enhancing effects of calorie restriction can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced activation of mTORC1 in Paneth cells during calorie restriction abolishes the ISC-augmenting effects of the niche. Finally, increased expression of bone stromal antigen 1 (Bst1) in Paneth cells—an ectoenzyme that produces the paracrine factor cyclic ADP ribose—mediates the effects of calorie restriction and rapamycin on ISC function. Our findings establish that mTORC1 non-cell-autonomously regulates stem-cell self-renewal, and highlight a significant role of the mammalian intestinal niche in coupling stem-cell function to organismal physiology.


Alternate JournalNature
PubMed ID22722868
PubMed Central IDPMC3387287
Grant ListR01 CA103866 / CA / NCI NIH HHS / United States
T32CA09216 / CA / NCI NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
CA103866 / CA / NCI NIH HHS / United States
T32 CA009216 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
CA129105 / CA / NCI NIH HHS / United States
R01 CA129105 / CA / NCI NIH HHS / United States
F32 AG032833 / AG / NIA NIH HHS / United States
1F32AG032833-01A1 / AG / NIA NIH HHS / United States