Ascl2 acts as an R-spondin/Wnt-responsive switch to control stemness in intestinal crypts
Open accessAbstract
The Wnt signaling pathway controls stem cell identity in the intestinal epithelium and in many other adult organs. The transcription factor Ascl2 (a Wnt target gene) is a master regulator of intestinal stem cell identity. It is unclear how the continuous Wnt gradient along the crypt axis is translated into discrete expression of Ascl2 and discrete specification of stem cells at crypt bottoms. We show that (1) Ascl2 is regulated in a direct autoactivatory loop, leading to a distinct on/off expression pattern, and (2) Wnt/R-spondin can activate this regulatory loop. This mechanism interprets the Wnt levels in the intestinal crypt and translates the continuous Wnt signal into a discrete Ascl2 "on" or "off" decision. In turn, Ascl2, together with β-catenin/Tcf, activates the genes fundamental to the stem cell state. In this manner, Ascl2 forms a transcriptional switch that is both Wnt responsive and Wnt dependent to define stem cell identity.
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The decline in Ascl2 expression upon aging is in line with Ascl2 being a central Wnt-responsive transcription factor.
“This finding is also in line with recent reports suggesting Ascl2 as a central Wnt-responsive transcription factor (Schuijers et al., 2015).”
From Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells (2017) · cites this paper as Schuijers et al., 2015
Ascl2 is a central Wnt-responsive transcription factor.
“This finding is also in line with recent reports suggesting Ascl2 as a central Wnt-responsive transcription factor (Schuijers et al., 2015).”
From Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells (2017) · cites this paper as Schuijers et al., 2015
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Wang, C., Shahi, P., Huang, J., Phan, N. N., Sun, Z., Lin, Y.-C., Lai, M., & Werb, Z. (2016) · Molecular and Clinical Oncology · doi:10.3892/mco.2016.1094 · Cited by 33 · see citing works
- Authors
- Schuijers, J., Junker, J. P., Mokry, M., Hatzis, P., Koo, B.-K., Sasselli, V., van der Flier, L. G., Cuppen, E., van Oudenaarden, A., & Clevers, H.
- Affiliations
- Royal Netherlands Academy of Arts and Sciences (NL)
- Alexander Fleming Biomedical Sciences Research Center (GR)
- Corresponding author
- Clevers, Hans
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 16
- Issue
- 2
- Pages
- 158-170
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W2107429180
- Cited by
- 273
- References
- 76
- Citations by year
- 2026: 16 · 2025: 25 · 2024: 20 · 2023: 17 · 2022: 22 · 2021: 22 · 2020: 29 · 2019: 26 · 2018: 35 · 2017: 35 · 2016: 16 · 2015: 10
- FWCI
- 13.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- ASCL2, R-spondin, Wnt signaling, intestinal stem cells, intestinal crypts, stem cell identity, transcriptional switch, intestinal epithelium
- MeSH terms
- Animals, Intestinal Mucosa, Stem Cells, Thrombospondins, Mice, Basic Helix-Loop-Helix Proteins, Wnt Signaling Pathway
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