PMID- 35021092
OWN - NLM
STAT- MEDLINE
DCOM- 20220214
LR  - 20220803
IS  - 2211-1247 (Electronic)
VI  - 38
IP  - 2
DP  - 2022 Jan 11
TI  - CDC42 controlled apical-basal polarity regulates intestinal stem cell to transit 
      amplifying cell fate transition via YAP-EGF-mTOR signaling.
PG  - 110009
LID - S2211-1247(21)01487-X [pii]
LID - 10.1016/j.celrep.2021.110009 [doi]
AB  - Epithelial polarity is controlled by a polarity machinery that includes Rho 
      GTPase CDC42 and Scribble/PAR. By using intestinal stem cell (ISC)-specific 
      deletion of CDC42 in olfactomedin-4 (Olfm4)-internal ribosome entry site 
      (IRES)-EGFP/CreERT2;CDC42(flox/flox) mice, we find that CDC42 loss initiated in 
      the ISCs causes a drastic hyperproliferation of transit amplifying (TA) cells and 
      disrupts epithelial polarity. CDC42-null crypts display expanded TA cell and 
      diminished ISC populations, accompanied by elevated Hippo signaling via 
      YAP/TAZ-Ereg (yes-associated protein/WW domain-containing transcription regulator 
      protein 1-epiregulin) and mechanistic target of rapamycin (mTOR) activation, 
      independent from canonical Wnt signaling. YAP/TAZ conditional knockout (KO) 
      restores the balance of ISC/TA cell populations and crypt proliferation but does 
      not rescue the polarity in CDC42-null small intestine. mTOR or epidermal growth 
      factor receptor (EGFR) inhibitor treatment of CDC42 KO mice exhibits similar 
      rescuing effects without affecting YAP/TAZ signaling. Inducible ablation of 
      Scribble in intestinal epithelial cells mimics that of CDC42 KO defects, 
      including crypt hyperplasia and Hippo signaling activation. Mammalian epithelial 
      polarity regulates ISC/TA cell fate and proliferation via a Hippo-Ereg-mTOR 
      cascade.
CI  - Copyright (c) 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Zhang, Zheng
AU  - Zhang Z
AD  - Division of Experimental Hematology and Cancer Biology, Children's Hospital 
      Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
FAU - Zhang, Feng
AU  - Zhang F
AD  - Division of Experimental Hematology and Cancer Biology, Children's Hospital 
      Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
FAU - Davis, Ashley Kuenzi
AU  - Davis AK
AD  - Division of Experimental Hematology and Cancer Biology, Children's Hospital 
      Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
FAU - Xin, Mei
AU  - Xin M
AD  - Division of Experimental Hematology and Cancer Biology, Children's Hospital 
      Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
FAU - Walz, Gerd
AU  - Walz G
AD  - Department of Medicine IV, University Freiburg Medical Center, Faculty of 
      Medicine, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany; 
      Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 
      Albertstrasse 19, 79104 Freiburg, Germany.
FAU - Tian, Weidong
AU  - Tian W
AD  - Division of Experimental Hematology and Cancer Biology, Children's Hospital 
      Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
FAU - Zheng, Yi
AU  - Zheng Y
AD  - Division of Experimental Hematology and Cancer Biology, Children's Hospital 
      Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. Electronic 
      address: yi.zheng@cchmc.org.
LA  - eng
GR  - P30 DK078392/DK/NIDDK NIH HHS/United States
GR  - R01 AG063967/AG/NIA NIH HHS/United States
GR  - R01 CA204895/CA/NCI NIH HHS/United States
GR  - R01 HL132211/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cell Rep
JT  - Cell reports
JID - 101573691
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Cdc42 protein, mouse)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.5.2 (cdc42 GTP-Binding Protein)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/metabolism
MH  - Animals
MH  - Cell Differentiation/physiology
MH  - Cell Lineage
MH  - Cell Polarity/genetics/*physiology
MH  - Cell Proliferation/physiology
MH  - Epidermal Growth Factor/metabolism
MH  - Female
MH  - Hippo Signaling Pathway/physiology
MH  - Intestines/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Signal Transduction/physiology
MH  - Stem Cells/*metabolism/physiology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Wnt Signaling Pathway/physiology
MH  - cdc42 GTP-Binding Protein/*metabolism/physiology
PMC - PMC8826493
MID - NIHMS1771083
OTO - NOTNLM
OT  - Cdc42
OT  - Hippo signaling
OT  - cell fate
OT  - intestinal stem cells
OT  - mTOR signaling
OT  - mouse model
OT  - polarity
COIS- Declaration of interests The authors declare no competing interests.
EDAT- 2022/01/13 06:00
MHDA- 2022/02/15 06:00
PMCR- 2022/02/09
CRDT- 2022/01/12 20:08
PHST- 2021/03/26 00:00 [received]
PHST- 2021/07/15 00:00 [revised]
PHST- 2021/10/26 00:00 [accepted]
PHST- 2022/01/12 20:08 [entrez]
PHST- 2022/01/13 06:00 [pubmed]
PHST- 2022/02/15 06:00 [medline]
PHST- 2022/02/09 00:00 [pmc-release]
AID - S2211-1247(21)01487-X [pii]
AID - 10.1016/j.celrep.2021.110009 [doi]
PST - ppublish
SO  - Cell Rep. 2022 Jan 11;38(2):110009. doi: 10.1016/j.celrep.2021.110009.