Intrinsic regulation of enteroendocrine fate by Numb

Sallé, Jérémy; Gervais, Louis; Boumard, Benjamin; Stefanutti, Marine; Siudeja, Katarzyna; Bardin, Allison J.

doi:10.15252/embj.201695622

Cited by 37 publications

(38 citation statements)

References 60 publications

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“…The wide range of physiological turnover time reflects the stochastic damage of absorptive enterocytes (ECs)—the main cells in the intestinal epithelium (Biteau et al , ; Jiang & Edgar, )—by exposure to pathogens and toxins present in food and chemicals and physical stress. The intestine also contains secretory enteroendocrine (EE) cells, which constitute only 10% of the intestinal population and renew themselves at a slower rate than ECs (de Navascués et al , ; Sallé et al , ; Parasram et al , ). Intestinal cell turnover is sustained by a small population of ISCs scattered throughout the epithelium that, as observed in other high‐turnover epithelia in mammals (Simons & Clevers, ), divide regularly and produce, with each division, one cell that differentiates and one that remains undifferentiated.…”

Section: Introductionmentioning

confidence: 99%

Notch and EGFR regulate apoptosis in progenitor cells to ensure gut homeostasis in Drosophila

et al. 2019

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The regenerative activity of adult stem cells carries a risk of cancer, particularly in highly renewable tissues. Members of the family of inhibitor of apoptosis proteins (IAPs) inhibit caspases and cell death, and are often deregulated in adult cancers; however, their roles in normal adult tissue homeostasis are unclear. Here, we show that regulation of the number of enterocyte‐committed progenitor (enteroblast) cells in the adult Drosophila involves a caspase‐mediated physiological apoptosis, which adaptively eliminates excess enteroblast cells produced by intestinal stem cells (ISCs) and, when blocked, can also lead to tumorigenesis. Importantly, we found that Diap1 is expressed by enteroblast cells and that loss and gain of Diap1 led to changes in enteroblast numbers. We also found that antagonistic interplay between Notch and EGFR signalling governs enteroblast life/death decisions via the Klumpfuss/WT1 and Lozenge/RUNX transcription regulators, which also regulate enteroblast differentiation and cell fate plasticity. These data provide new insights into how caspases drive adult tissue renewal and protect against the formation of tumours.

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Section: Introductionmentioning

confidence: 99%

Notch and EGFR regulate apoptosis in progenitor cells to ensure gut homeostasis in Drosophila

et al. 2019

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“…An important strategy utilized by dividing stem cells or progenitors to ensure binary cell fate decisions is asymmetric segregation of the endocytic protein Numb, an evolutionarily conserved Notch signaling antagonist, to one of the daughter cells ( Bultje et al, 2009 ; Conboy and Rando, 2002 ; Gunage et al, 2014 ; Lu et al, 1998 ; Luo et al, 2005 ; Rhyu et al, 1994 ; Sallé et al, 2017 ; Shen et al, 2002 ; Wang et al, 2006 ; Wu et al, 2017 ; Zhong et al, 1996 ). Numb acts as an adaptor to bridge the Notch receptor and its cofactor(s) with the endocytic machinery and reduces the surface pool of Notch by promoting its endocytosis ( Hutterer and Knoblich, 2005 ; Song and Lu, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

The retromer complex safeguards against neural progenitor-derived tumorigenesis by regulating Notch receptor trafficking

Wong

Gao

et al. 2018

eLife

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The correct establishment and maintenance of unidirectional Notch signaling are critical for the homeostasis of various stem cell lineages. However, the molecular mechanisms that prevent cell-autonomous ectopic Notch signaling activation and deleterious cell fate decisions remain unclear. Here we show that the retromer complex directly and specifically regulates Notch receptor retrograde trafficking in Drosophila neuroblast lineages to ensure the unidirectional Notch signaling from neural progenitors to neuroblasts. Notch polyubiquitination mediated by E3 ubiquitin ligase Itch/Su(dx) is inherently inefficient within neural progenitors, relying on retromer-mediated trafficking to avoid aberrant endosomal accumulation of Notch and cell-autonomous signaling activation. Upon retromer dysfunction, hypo-ubiquitinated Notch accumulates in Rab7+ enlarged endosomes, where it is ectopically processed and activated in a ligand-dependent manner, causing progenitor-originated tumorigenesis. Our results therefore unveil a safeguard mechanism whereby retromer retrieves potentially harmful Notch receptors in a timely manner to prevent aberrant Notch activation-induced neural progenitor dedifferentiation and brain tumor formation.

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“…This is surprising since asymmetric cell division is commonly observed in adult stem cells within many organs (25). Furthermore, asymmetric division of ISCs has been reported in Drosophila, mouse, and human (7,17,22,37,39,46). In fact, a majority of ISC divisions in these studies were asymmetric, ranging from 50 to 99%, and indicate that the asymmetric division mode plays a major role in the maintenance of the intestinal epithelium (7,17,22,37,46).…”

Section: Introductionmentioning

confidence: 89%

Asymmetric cell division-dominant neutral drift model for normal intestinal stem cell homeostasis

Sei

Feng

Chow

et al. 2019

American Journal of Physiology-Gastrointestinal and Liver Physi

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Sei Y, Feng J, Chow CC, Wank SA. Asymmetric cell divisiondominant neutral drift model for normal intestinal stem cell homeostasis. The normal intestinal epithelium is continuously regenerated at a rapid rate from actively cycling Lgr5-expressing intestinal stem cells (ISCs) that reside at the crypt base. Recent mathematical modeling based on several lineagetracing studies in mice shows that the symmetric cell division-dominant neutral drift model fits well with the observed in vivo growth of ISC clones and suggests that symmetric divisions are central to ISC homeostasis. However, other studies suggest a critical role for asymmetric cell division in the maintenance of ISC homeostasis in vivo. Here, we show that the stochastic branching and Moran process models with both a symmetric and asymmetric division mode not only simulate the stochastic growth of the ISC clone in silico but also closely fit the in vivo stem cell dynamics observed in lineage-tracing studies. In addition, the proposed model with highest probability for asymmetric division is more consistent with in vivo observations reported here and by others. Our in vivo studies of mitotic spindle orientations and lineage-traced progeny pairs indicate that asymmetric cell division is a dominant mode used by ISCs under normal homeostasis. Therefore, we propose the asymmetric cell division-dominant neutral drift model for normal ISC homeostasis.NEW & NOTEWORTHY The prevailing mathematical model suggests that intestinal stem cells (ISCs) divide symmetrically. The present study provides evidence that asymmetric cell division is the major contributor to ISC maintenance and thus proposes an asymmetric cell division-dominant neutral drift model. Consistent with this model, in vivo studies of mitotic spindle orientation and lineagetraced progeny pairs indicate that asymmetric cell division is the dominant mode used by ISCs under normal homeostasis.

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Intrinsic regulation of enteroendocrine fate by Numb

Cited by 37 publications

References 60 publications

Notch and EGFR regulate apoptosis in progenitor cells to ensure gut homeostasis in Drosophila

Notch and EGFR regulate apoptosis in progenitor cells to ensure gut homeostasis in Drosophila

The retromer complex safeguards against neural progenitor-derived tumorigenesis by regulating Notch receptor trafficking

Asymmetric cell division-dominant neutral drift model for normal intestinal stem cell homeostasis

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