Wnt signaling suppresses MAPK-driven proliferation of intestinal stem cells.

dc.contributor.author

Kabiri, Zahra

dc.contributor.author

Greicius, Gediminas

dc.contributor.author

Zaribafzadeh, Hamed

dc.contributor.author

Hemmerich, Amanda

dc.contributor.author

Counter, Christopher M

dc.contributor.author

Virshup, David M

dc.date.accessioned

2024-11-14T21:53:09Z

dc.date.available

2024-11-14T21:53:09Z

dc.date.issued

2018-08

dc.description.abstract

Intestinal homeostasis depends on a slowly proliferating stem cell compartment in crypt cells, followed by rapid proliferation of committed progenitor cells in the transit amplifying (TA) compartment. The balance between proliferation and differentiation in intestinal stem cells (ISCs) is regulated by Wnt/β-catenin signaling, although the mechanism remains unclear. We previously targeted PORCN, an enzyme essential for all Wnt secretion, and demonstrated that stromal production of Wnts was required for intestinal homeostasis. Here, a PORCN inhibitor was used to acutely suppress Wnt signaling. Unexpectedly, the treatment induced an initial burst of proliferation in the stem cell compartment of the small intestine, due to conversion of ISCs into TA cells with a loss of intrinsic ISC self-renewal. This process involved MAPK pathway activation, as the proliferating cells in the base of the intestinal crypt contained phosphorylated ERK1/2, and a MEK inhibitor attenuated the proliferation of ISCs and their differentiation into TA cells. These findings suggest a role for Wnt signaling in suppressing the MAPK pathway at the crypt base to maintain a pool of ISCs. The interaction between Wnt and MAPK pathways in vivo has potential therapeutic applications in cancer and regenerative medicine.

dc.identifier

99325

dc.identifier.issn

0021-9738

dc.identifier.issn

1558-8238

dc.identifier.uri

https://hdl.handle.net/10161/31636

dc.language

eng

dc.publisher

American Society for Clinical Investigation

dc.relation.ispartof

The Journal of clinical investigation

dc.relation.isversionof

10.1172/jci99325

dc.rights.uri

https://creativecommons.org/licenses/by-nc/4.0

dc.subject

Intestinal Mucosa

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Stem Cells

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Animals

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Mice, Inbred C57BL

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Mice, Transgenic

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Mice

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Benzeneacetamides

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Pyridines

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Acyltransferases

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Membrane Proteins

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Cell Differentiation

dc.subject

Cell Proliferation

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MAP Kinase Signaling System

dc.subject

Cell Lineage

dc.subject

Wnt Signaling Pathway

dc.title

Wnt signaling suppresses MAPK-driven proliferation of intestinal stem cells.

dc.type

Journal article

duke.contributor.orcid

Kabiri, Zahra|0000-0002-2192-0725

duke.contributor.orcid

Counter, Christopher M|0000-0003-0748-3079

duke.contributor.orcid

Virshup, David M|0000-0001-6976-850X

pubs.begin-page

3806

pubs.end-page

3812

pubs.issue

9

pubs.organisational-group

Duke

pubs.organisational-group

School of Medicine

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Basic Science Departments

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Clinical Science Departments

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Institutes and Centers

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Cell Biology

pubs.organisational-group

Pharmacology & Cancer Biology

pubs.organisational-group

Pathology

pubs.organisational-group

Pediatrics

pubs.organisational-group

Radiation Oncology

pubs.organisational-group

Surgery

pubs.organisational-group

Surgery, Surgical Sciences

pubs.organisational-group

Duke Cancer Institute

pubs.publication-status

Published

pubs.volume

128

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