PMID- 22586121
OWN - NLM
STAT- MEDLINE
DCOM- 20120827
LR  - 20220316
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 109
IP  - 23
DP  - 2012 Jun 5
TI  - Functional intestinal stem cells after Paneth cell ablation induced by the loss 
      of transcription factor Math1 (Atoh1).
PG  - 8965-70
LID - 10.1073/pnas.1201652109 [doi]
AB  - Intestinal epithelium has the capacity to self-renew and generate differentiated 
      cells through the existence of two types of epithelial stem cells: active crypt 
      base columnar cells (CBCs) and quiescent +4 cells. The behaviors of these cells 
      are regulated both by intrinsic programs and by extrinsic signals sent by 
      neighboring cells, which define the niche. It is clear that the beta-catenin pathway 
      acts as an essential intrinsic signal for the maintenance and proliferation of 
      CBC, and it was recently proposed that Paneth cells provide a crucial niche by 
      secreting Wingless/Int (Wnt) ligands. Here, we examined the effect of disrupting 
      the intestinal stem cell niche by inducible deletion of the transcription factor 
      Math1 (Atoh1), an essential driver of secretory cell differentiation. We found 
      that complete loss of Paneth cells attributable to Math1 deficiency did not 
      perturb the crypt architecture and allowed the maintenance and proliferation of 
      CBCs. Indeed, Math1-deficient crypt cells tolerated in vivo Paneth cell loss and 
      maintained active beta-catenin signaling but could not grow ex vivo without 
      exogenous Wnt, implying that, in vivo, underlying mucosal cells act as potential 
      niche. Upon irradiation, Math1-deficient crypt cells regenerated and CBCs 
      continued cycling. Finally, CBC stem cells deficient in adenomatous polyposis 
      coli (Apc) and Math1 were able to promote intestinal tumorigenesis. We conclude 
      that in vivo, Math1-deficient crypts counteract the absence of Paneth 
      cell-derived Wnts and prevent CBC stem cell exhaustion.
FAU - Durand, Aurelie
AU  - Durand A
AD  - Institut Cochin, Department of Endocrinology, Metabolism and Cancer, Universite 
      Paris Descartes, Centre National de la Recherche Scientifique Unite Mixte de 
      Recherche 8104, 75014 Paris, France.
FAU - Donahue, Bridgitte
AU  - Donahue B
FAU - Peignon, Gregory
AU  - Peignon G
FAU - Letourneur, Franck
AU  - Letourneur F
FAU - Cagnard, Nicolas
AU  - Cagnard N
FAU - Slomianny, Christian
AU  - Slomianny C
FAU - Perret, Christine
AU  - Perret C
FAU - Shroyer, Noah F
AU  - Shroyer NF
FAU - Romagnolo, Beatrice
AU  - Romagnolo B
LA  - eng
GR  - R01 CA142826/CA/NCI NIH HHS/United States
GR  - R01 DK092306/DK/NIDDK NIH HHS/United States
GR  - CA142826/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120514
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Atoh1 protein, mouse)
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (Wnt Proteins)
RN  - 0 (beta Catenin)
SB  - IM
MH  - Animals
MH  - Basic Helix-Loop-Helix Transcription Factors/*deficiency
MH  - Immunohistochemistry
MH  - In Situ Hybridization
MH  - Intestinal Mucosa/*cytology
MH  - Mice
MH  - Microarray Analysis
MH  - Microscopy, Electron
MH  - Paneth Cells/*cytology
MH  - Polymerase Chain Reaction
MH  - Signal Transduction/*physiology
MH  - Stem Cells/*ultrastructure
MH  - Wnt Proteins/deficiency
MH  - beta Catenin/*metabolism
PMC - PMC3384132
COIS- The authors declare no conflict of interest.
EDAT- 2012/05/16 06:00
MHDA- 2012/08/28 06:00
PMCR- 2012/12/05
CRDT- 2012/05/16 06:00
PHST- 2012/05/16 06:00 [entrez]
PHST- 2012/05/16 06:00 [pubmed]
PHST- 2012/08/28 06:00 [medline]
PHST- 2012/12/05 00:00 [pmc-release]
AID - 1201652109 [pii]
AID - 201201652 [pii]
AID - 10.1073/pnas.1201652109 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2012 Jun 5;109(23):8965-70. doi: 
      10.1073/pnas.1201652109. Epub 2012 May 14.