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

Ömer H. Yilmaz, Pekka Katajisto, Dudley W. Lamming, Yetis Gültekin, Khristian E. Bauer-Rowe, Shomit Sengupta, Kivanc Birsoy, Abdulmetin Dursun, V. Onur Yilmaz, Martin Selig, G. Petur Nielsen, Mari Mino-Kenudson, Lawrence R. Zukerberg, Atul K. Bhan, Vikram Deshpande and David M. Sabatini ()
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Ömer H. Yilmaz: Massachusetts General Hospital and Harvard Medical School
Pekka Katajisto: Whitehead Institute for Biomedical Research, Boston, Massachusetts 02142; Department of Biology, MIT, Cambridge, Massachusetts 02139; Howard Hughes Medical Institute, MIT, Cambridge, Massachusetts 02139; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142; The David H. Koch Institute for Integrative Cancer Research at MIT
Dudley W. Lamming: Whitehead Institute for Biomedical Research, Boston, Massachusetts 02142; Department of Biology, MIT, Cambridge, Massachusetts 02139; Howard Hughes Medical Institute, MIT, Cambridge, Massachusetts 02139; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142; The David H. Koch Institute for Integrative Cancer Research at MIT
Yetis Gültekin: Massachusetts General Hospital and Harvard Medical School
Khristian E. Bauer-Rowe: Whitehead Institute for Biomedical Research, Boston, Massachusetts 02142; Department of Biology, MIT, Cambridge, Massachusetts 02139; Howard Hughes Medical Institute, MIT, Cambridge, Massachusetts 02139; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142; The David H. Koch Institute for Integrative Cancer Research at MIT
Shomit Sengupta: Whitehead Institute for Biomedical Research, Boston, Massachusetts 02142; Department of Biology, MIT, Cambridge, Massachusetts 02139; Howard Hughes Medical Institute, MIT, Cambridge, Massachusetts 02139; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142; The David H. Koch Institute for Integrative Cancer Research at MIT
Kivanc Birsoy: Whitehead Institute for Biomedical Research, Boston, Massachusetts 02142; Department of Biology, MIT, Cambridge, Massachusetts 02139; Howard Hughes Medical Institute, MIT, Cambridge, Massachusetts 02139; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142; The David H. Koch Institute for Integrative Cancer Research at MIT
Abdulmetin Dursun: Massachusetts General Hospital and Harvard Medical School
V. Onur Yilmaz: Whitehead Institute for Biomedical Research, Boston, Massachusetts 02142; Department of Biology, MIT, Cambridge, Massachusetts 02139; Howard Hughes Medical Institute, MIT, Cambridge, Massachusetts 02139; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142; The David H. Koch Institute for Integrative Cancer Research at MIT
Martin Selig: Massachusetts General Hospital and Harvard Medical School
G. Petur Nielsen: Massachusetts General Hospital and Harvard Medical School
Mari Mino-Kenudson: Massachusetts General Hospital and Harvard Medical School
Lawrence R. Zukerberg: Massachusetts General Hospital and Harvard Medical School
Atul K. Bhan: Massachusetts General Hospital and Harvard Medical School
Vikram Deshpande: Massachusetts General Hospital and Harvard Medical School
David M. Sabatini: Whitehead Institute for Biomedical Research, Boston, Massachusetts 02142; Department of Biology, MIT, Cambridge, Massachusetts 02139; Howard Hughes Medical Institute, MIT, Cambridge, Massachusetts 02139; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142; The David H. Koch Institute for Integrative Cancer Research at MIT

Nature, 2012, vol. 486, issue 7404, 490-495

Abstract: Abstract 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.

Date: 2012
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DOI: 10.1038/nature11163

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