Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling

Wong, Vivian W.Y.; Stange, Daniel E.; Page, Mahalia E.; Buczacki, Simon; Wabik, Agnieszka; Itami, Satoshi; Wetering, Marc van de; Poulsom, Richard; Wright, Nicholas; Trotter, Matthew; Watt, Fiona M.; Winton, Doug J.; Clevers, Hans; Jensen, Kim B.

doi:10.1038/ncb2464

Cited by 369 publications

(393 citation statements)

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“…[25][26][27] . It has been suggested that Akt activates Wnt/b-catenin signalling, which plays the dominant role in Lgr5 þ stem cell self-renewal 23,46 . Here we demonstrated the important role of the Myh9-Rac1-PAK1-Akt signalling pathway in maintenance of Lgr5 þ stem cells.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

“…It has been shown that Akt activity, as shown by Akt phosphorylation, is critical for the expansion of intestinal crypts and epithelial stem cells [23][24][25] . Therefore, we hypothesized that blebbistatin might activate Akt in Lgr5 þ stem cells.…”

Section: Dissociation-induced Myh9 Expression Restricts Crypt Growthmentioning

confidence: 99%

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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“…The crypt base harbors intestinal stem cells and displays high EGFR signaling (40). It has been shown that intestinal stem cell proliferation is driven by EGFR and downstream ERK activation in both mammals and fruit flies (40 -42).…”

Section: Resultsmentioning

confidence: 99%

Tuning of Protein Kinase Circuitry by p38α Is Vital for Epithelial Tissue Homeostasis

Caballero-Franco

Choo

Sano

et al. 2013

Journal of Biological Chemistry

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Background:The protein kinase p38␣ mediates cellular responses to stress and immune signals. Results: Loss of p38␣ in epithelial cells results in aberrant activation of multiple protein kinases and disrupts tissue homeostasis. Conclusion: Epithelial tissue homeostasis requires cross-regulatory interactions between p38␣ and other protein kinases. Significance: These findings provide clues about how to prevent the adverse effects of p38 inhibitors.

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“…Intestinal stem cells give rise to all other intestinal epithelial lineages and maintain their own population indefinitely (1). A number of transgenic reporters has been used in lineage tracing assays to show stem cell activity arising from the base of the crypt (2)(3)(4)(5)(6)(7)(8), and all have been reported to overlap with crypt base columnar cells (9), which cooccupy the bottom of crypts with differentiated Paneth cells. Intestinal stem cells marked by leucine rich repeat containing G protein coupled receptor 5 (Lgr5) expression have been the most extensively characterized; these cells maintain their own population through symmetric divisions (10), and when they leave the niche, they give rise to differentiated crypt cells, including a transit amplifying population that ultimately supplies differentiated cells onto luminal projections called villi.…”

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confidence: 99%

YY1 is indispensable for Lgr5 ⁺ intestinal stem cell renewal

Perekatt

Valdez

Davila

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The intestinal stem cell fuels the highest rate of tissue turnover in the body and has been implicated in intestinal disease and cancer; understanding the regulatory mechanisms controlling intestinal stem cell physiology is of great importance. Here, we provide evidence that the transcription factor YY1 is essential for intestinal stem cell renewal. We observe that YY1 loss skews normal homeostatic cell turnover, with an increase in proliferating crypt cells and a decrease in their differentiated villous progeny. Increased crypt cell numbers come at the expense of Lgr5 + stem cells. On YY1 deletion, Lgr5 + cells accelerate their commitment to the differentiated population, exhibit increased levels of apoptosis, and fail to maintain stem cell renewal. Loss of Yy1 in the intestine is ultimately fatal. Mechanistically, YY1 seems to play a role in stem cell energy metabolism, with mitochondrial complex I genes bound directly by YY1 and their transcript levels decreasing on YY1 loss. These unappreciated YY1 functions broaden our understanding of metabolic regulation in intestinal stem cell homeostasis. (9), which cooccupy the bottom of crypts with differentiated Paneth cells. Intestinal stem cells marked by leucine rich repeat containing G protein coupled receptor 5 (Lgr5) expression have been the most extensively characterized; these cells maintain their own population through symmetric divisions (10), and when they leave the niche, they give rise to differentiated crypt cells, including a transit amplifying population that ultimately supplies differentiated cells onto luminal projections called villi.Intestinal stem cells are of great importance to human health and regenerative medicine. Mouse models of human colorectal cancer show that intestinal stem cells can function as cells of origin for cancer (11,12). There is a clear imperative to understand the regulatory mechanisms governing intestinal stem cell function. Recent work has shown that intestinal stem cells from both flies and humans are sensitive to the metabolic state of the organism and has implicated cellular metabolism as a critical regulatory input of stem cell homeostasis (13-16). Intestinal stem cells were observed to exhibit higher levels of glycolysis than oxidative phosphorylation compared with their differentiated progeny (17), and the oxidative state of intestinal stem cells impacts the ability of the cells to undergo transformation (18). Caloric restriction was recently shown to increase intestinal stem cell numbers (16). In Drosophila, intestinal stem cell expression of the fly homolog to PGC-1α, a metabolic coregulator, is even coupled to the organism's lifespan (19). These exciting advances highlight a great need to identify additional regulators of intestinal stem cell metabolism.YY1 is a zinc finger transcription factor first discovered for its function in viral gene expression (20, 21) and cloned during investigations of viral (22), immunoglobulin (23), and ribosomal (24) gene expression. YY1 has since been implicated in a number of proc...

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Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling

Cited by 369 publications

References 40 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

Tuning of Protein Kinase Circuitry by p38α Is Vital for Epithelial Tissue Homeostasis

YY1 is indispensable for Lgr5 ⁺ intestinal stem cell renewal

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Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling

Cited by 369 publications

References 40 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

Tuning of Protein Kinase Circuitry by p38α Is Vital for Epithelial Tissue Homeostasis

YY1 is indispensable for Lgr5 + intestinal stem cell renewal

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YY1 is indispensable for Lgr5 ⁺ intestinal stem cell renewal