Transcription Factor Achaete Scute-Like 2 Controls Intestinal Stem Cell Fate

Flier, Laurens G. van der; Gijn, Mariëlle van; Hatzis, Pantelis; Kujala, Pekka; Haegebarth, Andrea; Stange, Daniel E.; Begthel, Harry; Born, Marise Ph.; Guryev, Victor; Oving, Irma M.; Es, Johan H. van; Barker, Nick; Peters, Peter J.; Wetering, Marc van de; Clevers, Hans

doi:10.1016/j.cell.2009.01.031

Cited by 638 publications

(589 citation statements)

References 49 publications

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“…As shown in Fig. 3g, blebbistatin stimulated the expressions of the pluripotency marker genes Lgr5 and Ascl2 in Lgr5 þ intestinal stem cells 2,28 . To further support the notion that blebbistatin promotes the survival and pluripotency of Lgr5 þ stem cells via Akt activation, we examined whether the PI3K-specific inhibitor LY294002, which can block Akt activation 29 , could attenuate the effects of blebbistatin.…”

Section: Dissociation-induced Myh9 Expression Restricts Crypt Growthmentioning

confidence: 69%

The non-muscle-myosin-II heavy chain Myh9 mediates colitis-induced epithelium injury by restricting Lgr5+ stem cells

Zhao

et al. 2015

Nat Commun

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Lgr5 þ stem cells are crucial to gut epithelium homeostasis, and therapies targeting these cells hold promise for treatment of gastrointestinal diseases. Here we report that the non-muscle-myosin-II (NMII) heavy chain Myh9 accumulates at epithelial injury sites in mice distal colon treated with dextran sulphate sodium (DSS). Gut-epithelium-specific Myh9 monoallelic deletion alleviates DSS-induced colonic crypt damage and acute colitis. Consistently, the NMII inhibitor blebbistatin can improve the survival of Lgr5 þ stem cells and the growth of Lgr5 organoids. Mechanistically, inhibition of NMII by blebbistatin or Myh9 monoallelic deletion activates Akt through Rac1 and PAK1, which is essential for the survival and pluripotency of Lgr5 þ cells. These results establish a critical role of the Myh9-Rac1-PAK1-Akt pathway in the maintenance of Lgr5 þ stem cells. As blebbistatin can mitigate DSS-induced colitis and preserve Lgr5 þ colonic stem cells in vivo, our findings provide a potential therapeutic intervention of gastrointestinal epithelium injury and degenerative diseases.

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Section: Dissociation-induced Myh9 Expression Restricts Crypt Growthmentioning

confidence: 69%

The non-muscle-myosin-II heavy chain Myh9 mediates colitis-induced epithelium injury by restricting Lgr5+ stem cells

Zhao

et al. 2015

Nat Commun

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“…Such uncoupling between Lgr5 and Olfm4 expression was puzzling as Olfm4 was described as a robust marker of Lgr5-positive ISCs. 25 To clarify this point, we first looked at Olfm4 expression by in situ hybridization. Most crypt bases were devoid of Olfm4 expression, and consisted of packed lysozyme-positive paneth cells (Figure 2e Figure S1B, arrow).…”

Section: Resultsmentioning

confidence: 99%

Ribosome biogenesis dysfunction leads to p53-mediated apoptosis and goblet cell differentiation of mouse intestinal stem/progenitor cells

et al. 2015

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International audienceRibosome biogenesis is an essential cellular process. Its impairment is associated with developmental defects and increased risk of cancer. The in vivo cellular responses to defective ribosome biogenesis and the underlying molecular mechanisms are still incompletely understood. In particular, the consequences of impaired ribosome biogenesis within the intestinal epithelium in mammals have not been investigated so far. Here we adopted a genetic approach to investigate the role of Notchless (NLE), an essential actor of ribosome biogenesis, in the adult mouse intestinal lineage. Nle deficiency led to defects in the synthesis of large ribosomal subunit in crypts cells and resulted in the rapid elimination of intestinal stem cells and progenitors through distinct types of cellular responses, including apoptosis, cell cycle arrest and biased differentiation toward the goblet cell lineage. Similar observations were made using the rRNA transcription inhibitor CX-5461 on intestinal organoids culture. Importantly, we found that p53 activation was responsible for most of the cellular responses observed, including differentiation toward the goblet cell lineage. Moreover, we identify the goblet cell-specific marker Muc2 as a direct transcriptional target of p53. Nle-deficient ISCs and progenitors disappearance persisted in the absence of p53, underlying the existence of p53-independent cellular responses following defective ribosome biogenesis. Our data indicate that NLE is a crucial factor for intestinal homeostasis and provide new insights into how perturbations of ribosome biogenesis impact on cell fate decisions within the intestinal epithelium

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“…The genes included Paneth cell markers ephrin receptor B3 ( EphB3 ) and lysozyme 1 ( Lyz1 ) (van Es et al ., 2005) or genes with broader expression in various crypt cells such as division cycle associated 7 ( Cdca7 ), ephrin receptor B2 ( EphB2 ), naked cuticle homolog 1 ( Nkd1 ), and SRY (sex determining region Y)‐box 9 ( Sox9 ) (Batlle et al ., 2002; Schuijers et al ., 2015; Stancikova et al ., 2015). Remarkably, the most robust downregulation was recorded for three genes that encode Wnt signaling‐activated markers of ISCs achaete‐scute complex homolog 2 ( Ascl2 ), Lgr5 , and Troy (Fafilek et al ., 2013; van der Flier et al ., 2009). Interestingly, olfactomedin 4 ( Olfm4 ), which represents another ISC marker but whose expression is not regulated by Wnt signaling (van der Flier et al ., 2009), was decreased only moderately.…”

Section: Resultsmentioning

confidence: 99%

“…Remarkably, the most robust downregulation was recorded for three genes that encode Wnt signaling‐activated markers of ISCs achaete‐scute complex homolog 2 ( Ascl2 ), Lgr5 , and Troy (Fafilek et al ., 2013; van der Flier et al ., 2009). Interestingly, olfactomedin 4 ( Olfm4 ), which represents another ISC marker but whose expression is not regulated by Wnt signaling (van der Flier et al ., 2009), was decreased only moderately. Finally, expression of keratin 20 ( Krt20 ), which marks terminally differentiated cells, was at the first time point substantially increased, but at the later time point returned to its original level (Fig.…”

Section: Resultsmentioning

confidence: 99%

Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity

Janečková

Fafílek

Krausová

et al. 2016

Genesis

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SummaryThe Wnt pathway plays a crucial role in self‐renewal and differentiation of cells in the adult gut. In the present study, we revealed the functional consequences of inhibition of canonical Wnt signaling in the intestinal epithelium. The study was based on generation of a novel transgenic mouse strain enabling inducible expression of an N‐terminally truncated variant of nuclear Wnt effector T cell factor 4 (TCF4). The TCF4 variant acting as a dominant negative (dn) version of wild‐type (wt) TCF4 protein decreased transcription of β‐catenin‐TCF4‐responsive genes. Interestingly, suppression of Wnt/β‐catenin signaling affected asymmetric division of intestinal stem cells (ISCs) rather than proliferation. ISCs expressing the transgene underwent several rounds of division but lost their clonogenic potential and migrated out of the crypt. Expression profiling of crypt cells revealed that besides ISC‐specific markers, the dnTCF4 production downregulated expression levels of epithelial genes produced in other crypt cells including markers of Paneth cells. Additionally, in Apc conditional knockout mice, dnTCF activation efficiently suppressed growth of Apc‐deficient tumors. In summary, the generated mouse strain represents a convenient tool to study cell‐autonomous inhibition of β‐catenin‐Tcf‐mediated transcription. genesis 54:101–114, 2016. © 2016 The Authors genesis Published by Wiley Periodicals, Inc.

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Transcription Factor Achaete Scute-Like 2 Controls Intestinal Stem Cell Fate

Cited by 638 publications

References 49 publications

The non-muscle-myosin-II heavy chain Myh9 mediates colitis-induced epithelium injury by restricting Lgr5+ stem cells

The non-muscle-myosin-II heavy chain Myh9 mediates colitis-induced epithelium injury by restricting Lgr5+ stem cells

Ribosome biogenesis dysfunction leads to p53-mediated apoptosis and goblet cell differentiation of mouse intestinal stem/progenitor cells

Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity

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