Notch signals control the fate of immature progenitor cells in the intestine

Fre, Silvia; Huyghe, Mathilde; Mourikis, Philippos; Robine, Sylvie; Louvard, Daniel; Artavanis‐Tsakonas, Spyros

doi:10.1038/nature03589

Cited by 818 publications

(716 citation statements)

References 31 publications

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“…23 Contrary to Drosophila, 38 Nle loss of function does not seem to interfere with the Notch pathway in the mouse hematopoietic 23 and intestinal (this study) lineages. Indeed, although increasing or decreasing Notch activity systematically results in strong variations of Hes1 expression levels in the intestinal crypt cells, [39][40][41][42][43] Hes1 mRNA levels were unchanged following Nle inactivation in the intestinal epithelium (Figure 3c and data not shown). Interestingly, premature differentiation toward the goblet cell lineage of intestinal stem/ progenitor cells is observed when Notch activity is inhibited.…”

Section: Discussionmentioning

confidence: 91%

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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Section: Discussionmentioning

confidence: 91%

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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“…Post-natal gut specific inactivation of RBP-J results in the complete loss of proliferating transient amplifying (TA) cells [124]. In a reciprocal experiment, expression of activated Notch1 (NICD) in the gut inhibits differentiation of crypt progenitors [125]. These genetic experiments establish Notch signaling as a gatekeeper for intestinal crypt cells in mice.…”

Section: Notch Signaling In Development and Differentiationmentioning

confidence: 97%

The Notch signaling pathway: Transcriptional regulation at Notch target genes

Borggrefe

Oswald

2009

Cell. Mol. Life Sci.

584

499

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. The Notch gene encodes a transmembrane receptor that gave the name to the evolutionary highly conserved Notch signaling cascade. It plays a pivotal role in the regulation of many fundamental cellular processes such as proliferation, stem cell maintenance and differentiation during embryonic and adult development. After specific ligand binding, the intracellular part of the Notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor RBP-J. In the absence of activated Notch, RBP-J represses Notch target genes by recruiting a corepressor complex. Here, we review Notch signaling with a focus on gene regulatory events at Notch target genes. This is of utmost importance to understand Notch signaling since certain RBP-J associated cofactors and particular epigenetic marks determine the specificity of Notch target gene expression in different cell types. We subsequently summarize the current knowledge about Notch target genes and the physiological significance of Notch signaling in development and cancer.

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“…Notch signaling plays a key role specifying differentiation in the intestinal epithelium in developing and adult mice [18], [19], [20], [21]. Previously we have shown that conditional expression of an activated Notch mutant fused to Enhanced Green Fluorescent Protein (EGFP) (ICD-E) in the intestine of adult mice results in a transient increase in goblet cells on the villus, within 24 hours of Notch activation, followed by crypt apoptosis and shedding of the recombinant epithelium [20].…”

Section: Introductionmentioning

confidence: 99%

Intestinal Activation of Notch Signaling Induces Rapid Onset Hepatic Steatosis and Insulin Resistance

2011

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Here we investigate the effects of expressing an activated mutant of Notch (ICD-E) in an inducible transgenic mouse model. Hepatic expression of ICD-E in adult animals has no detectable phenotype, but simultaneous induction of ICD-E in both the liver and small intestine results in hepatic steatosis, lipogranuloma formation and mild insulin resistance within 96 hours. This supports work that suggests that fatty liver disease may result from disruption of the gut-liver axis. In the intestine, ICD-E expression is known to produce a transient change in the proportion of goblet cells followed by shedding of the recombinant epithelium. We report additional intestinal transcriptional changes following ICD-E expression, finding significant transcriptional down-regulation of rpL29 (ribosomal protein L29), which is implicated in the regulation of intestinal flora. These results provide further evidence of a gut-liver axis in the development of fatty liver disease and insulin resistance and validate a new model for future studies of hepatic steatosis.

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Notch signals control the fate of immature progenitor cells in the intestine

Cited by 818 publications

References 31 publications

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

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

The Notch signaling pathway: Transcriptional regulation at Notch target genes

Intestinal Activation of Notch Signaling Induces Rapid Onset Hepatic Steatosis and Insulin Resistance

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