PMID- 26503053
OWN - NLM
STAT- MEDLINE
DCOM- 20160426
LR  - 20220330
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Linking)
VI  - 526
IP  - 7575
DP  - 2015 Oct 29
TI  - Yap-dependent reprogramming of Lgr5(+) stem cells drives intestinal regeneration 
      and cancer.
PG  - 715-8
LID - 10.1038/nature15382 [doi]
AB  - The gut epithelium has remarkable self-renewal capacity that under homeostatic 
      conditions is driven by Wnt signalling in Lgr5(+) intestinal stem cells (ISCs). 
      However, the mechanisms underlying ISC regeneration after injury remain poorly 
      understood. The Hippo signalling pathway mediates tissue growth and is important 
      for regeneration. Here we demonstrate in mice that Yap, a downstream 
      transcriptional effector of Hippo, is critical for recovery of intestinal 
      epithelium after exposure to ionizing radiation. Yap transiently reprograms 
      Lgr5(+) ISCs by suppressing Wnt signalling and excessive Paneth cell 
      differentiation, while promoting cell survival and inducing a regenerative 
      program that includes Egf pathway activation. Accordingly, growth of 
      Yap-deficient organoids is rescued by the Egfr ligand epiregulin, and we find 
      that non-cell-autonomous production of stromal epiregulin may compensate for Yap 
      loss in vivo. Consistent with key roles for regenerative signalling in 
      tumorigenesis, we further demonstrate that Yap inactivation abolishes adenomas in 
      the Apc(Min) mouse model of colon cancer, and that Yap-driven expansion of 
      Apc(-/-) organoids requires the Egfr module of the Yap regenerative program. 
      Finally, we show that in vivo Yap is required for progression of early Apc mutant 
      tumour-initiating cells, suppresses their differentiation into Paneth cells, and 
      induces a regenerative program and Egfr signalling. Our studies reveal that upon 
      tissue injury, Yap reprograms Lgr5(+) ISCs by inhibiting the Wnt homeostatic 
      program, while inducing a regenerative program that includes activation of Egfr 
      signalling. Moreover, our findings reveal a key role for the Yap regenerative 
      pathway in driving cancer initiation.
FAU - Gregorieff, Alex
AU  - Gregorieff A
AD  - Centre for Systems Biology, Lunenfeld Tanenbaum Research Institute, Mount Sinai 
      Hospital, Toronto, Ontario M5G 1X5, Canada.
FAU - Liu, Yu
AU  - Liu Y
AD  - Centre for Systems Biology, Lunenfeld Tanenbaum Research Institute, Mount Sinai 
      Hospital, Toronto, Ontario M5G 1X5, Canada.
AD  - Department of Molecular Genetics, University of Toronto, Ontario M5S 1A8, Canada.
FAU - Inanlou, Mohammad R
AU  - Inanlou MR
AD  - Centre for Systems Biology, Lunenfeld Tanenbaum Research Institute, Mount Sinai 
      Hospital, Toronto, Ontario M5G 1X5, Canada.
FAU - Khomchuk, Yuliya
AU  - Khomchuk Y
AD  - Centre for Systems Biology, Lunenfeld Tanenbaum Research Institute, Mount Sinai 
      Hospital, Toronto, Ontario M5G 1X5, Canada.
FAU - Wrana, Jeffrey L
AU  - Wrana JL
AD  - Centre for Systems Biology, Lunenfeld Tanenbaum Research Institute, Mount Sinai 
      Hospital, Toronto, Ontario M5G 1X5, Canada.
AD  - Department of Molecular Genetics, University of Toronto, Ontario M5S 1A8, Canada.
LA  - eng
SI  - GEO/GSE66567
GR  - MOP-106672/Canadian Institutes of Health Research/Canada
GR  - MOP-12860/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151021
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Epiregulin)
RN  - 0 (Ereg protein, mouse)
RN  - 0 (Lgr5 protein, mouse)
RN  - 0 (Phosphoproteins)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (YAP-Signaling Proteins)
RN  - 0 (Yap1 protein, mouse)
RN  - EC 2.7.10.1 (EGFR protein, mouse)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/deficiency/*metabolism
MH  - Adenoma/metabolism/pathology
MH  - Animals
MH  - Cell Cycle Proteins
MH  - *Cell Differentiation/radiation effects
MH  - Cell Survival/radiation effects
MH  - Cell Transformation, Neoplastic
MH  - Colonic Neoplasms/metabolism/*pathology
MH  - Disease Models, Animal
MH  - Epiregulin/metabolism
MH  - ErbB Receptors/metabolism
MH  - Female
MH  - Hippo Signaling Pathway
MH  - Homeostasis/radiation effects
MH  - Intestinal Mucosa/metabolism
MH  - Intestines/*cytology/radiation effects
MH  - Male
MH  - Mice
MH  - Neoplastic Stem Cells/cytology/metabolism/pathology
MH  - Organoids/metabolism
MH  - Paneth Cells/cytology/radiation effects
MH  - Phosphoproteins/deficiency/*metabolism
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Radiation, Ionizing
MH  - Receptors, G-Protein-Coupled/*metabolism
MH  - *Regeneration/radiation effects
MH  - Stem Cells/cytology/*metabolism/radiation effects
MH  - Wnt Signaling Pathway
MH  - YAP-Signaling Proteins
EDAT- 2015/10/28 06:00
MHDA- 2016/04/27 06:00
CRDT- 2015/10/28 06:00
PHST- 2014/05/14 00:00 [received]
PHST- 2015/08/07 00:00 [accepted]
PHST- 2015/10/28 06:00 [entrez]
PHST- 2015/10/28 06:00 [pubmed]
PHST- 2016/04/27 06:00 [medline]
AID - nature15382 [pii]
AID - 10.1038/nature15382 [doi]
PST - ppublish
SO  - Nature. 2015 Oct 29;526(7575):715-8. doi: 10.1038/nature15382. Epub 2015 Oct 21.