Distinct levels of Notch activity for commitment and terminal differentiation of stem cells in the adult fly intestine

Perdigoto, Carolina N.; Schweisguth, François; Bardin, Allison J.

doi:10.1242/dev.065292

Cited by 142 publications

(162 citation statements)

References 63 publications

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“…In contrast to our observation in the epithelium of wing imaginal discs, Gmd homozygous clones behave cell-autonomously in the stem cells of the adult fly intestine (32). Thus, the intercellularly supplied GDP-L-fucose is not a general property of Drosophila tissues and cells.…”

Section: Discussioncontrasting

confidence: 99%

“…To address these issues, we next examined whether Gmd and Gmer function cell-autonomously or cell-nonautonomously in vivo, because these mutants should behave cell-nonautonomously if GDP-Lfucose is transferred intercellularly. Although the cell-nonautonomous behavior of Gmd was previously reported (18,19,32), this phenomenon has not been examined in detail.…”

Section: Resultsmentioning

confidence: 98%

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Rescue of Notch signaling in cells incapable of GDP- l -fucose synthesis by gap junction transfer of GDP- l -fucose in Drosophila

Ayukawa¹,

Matsumoto

Ishikawa

et al. 2012

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

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Notch (N) is a transmembrane receptor that mediates cell-cell interactions to determine many cell-fate decisions. N contains EGF-like repeats, many of which have an O-fucose glycan modification that regulates N-ligand binding. This modification requires GDP-L-fucose as a donor of fucose. The GDP-L-fucose biosynthetic pathways are well understood, including the de novo pathway, which depends on GDP-mannose 4,6 dehydratase (Gmd) and GDP-4-keto-6-deoxy-D-mannose 3,5-epimerase/4-reductase (Gmer). However, the potential for intercellularly supplied GDP-L-fucose and the molecular basis of such transportation have not been explored in depth. To address these points, we studied the genetic effects of mutating Gmd and Gmer on fucose modifications in Drosophila. We found that these mutants functioned cell-nonautonomously, and that GDP-L-fucose was supplied intercellularly through gap junctions composed of Innexin-2. GDP-L-fucose was not supplied through body fluids from different isolated organs, indicating that the intercellular distribution of GDP-L-fucose is restricted within a given organ. Moreover, the gap junction-mediated supply of GDP-L-fucose was sufficient to support the fucosylation of N-glycans and the O-fucosylation of the N EGF-like repeats. Our results indicate that intercellular delivery is a metabolic pathway for nucleotide sugars in live animals under certain circumstances.sugar metabolism | intercellular transport

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Section: Discussioncontrasting

confidence: 99%

Section: Resultsmentioning

confidence: 98%

Rescue of Notch signaling in cells incapable of GDP- l -fucose synthesis by gap junction transfer of GDP- l -fucose in Drosophila

Ayukawa¹,

Matsumoto

Ishikawa

et al. 2012

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

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“…Although determining the efficiency of glucosylation and xylosylation provides additional insight to investigating the role of O-glucosylation on Notch activity, there are still unanswered questions. The exact molecular mechanisms of how O-glucosylation promotes Notch activity (29,45,53) and xylosylation of the O-glucose inhibits Notch activity (33) are yet to be determined.…”

Section: Eics Of O-glucose Sites Represented By Peptides Also Containmentioning

confidence: 99%

Mapping Sites of O-Glycosylation and Fringe Elongation on Drosophila Notch

Harvey

Rana

Moss

et al. 2016

Journal of Biological Chemistry

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Glycosylation of the Notch receptor is essential for its activity and serves as an important modulator of signaling. Three major forms of O-glycosylation are predicted to occur at consensus sites within the epidermal growth factor-like repeats in the extracellular domain of the receptor: O-fucosylation, O-glucosylation, and O-GlcNAcylation. We have performed comprehensive mass spectral analyses of these three types of O-glycosylation on Drosophila Notch produced in S2 cells and identified peptides containing all 22 predicted O-fucose sites, all 18 predicted O-glucose sites, and all 18 putative O-GlcNAc sites. Using semiquantitative mass spectral methods, we have evaluated the occupancy and relative amounts of glycans at each site. The majority of the O-fucose sites were modified to high stoichiometries. Upon expression of the ␤3-N-acetylglucosaminyltransferase Fringe with Notch, we observed varying degrees of elongation beyond O-fucose monosaccharide, indicating that Fringe preferentially modifies certain sites more than others. Rumi modified O-glucose sites to high stoichiometries, although elongation of the O-glucose was site-specific. Although the current putative consensus sequence for O-GlcNAcylation predicts 18 O-GlcNAc sites on Notch, we only observed apparent O-GlcNAc modification at five sites. In addition, we performed mass spectral analysis on endogenous Notch purified from Drosophila embryos and found that the glycosylation states were similar to those found on Notch from S2 cells. These data provide foundational information for future studies investigating the mechanisms of how O-glycosylation regulates Notch activity.

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“…Low levels of Notch activity in progenitor cells (EBs) is believed to be required for their differentiation into EEs while high levels of the pathway are necessary for ECs specification (Ohlstein and Spradling, 2006) (Micchelli and Perrimon, 2006) (Bardin et al, 2010) (Perdigoto et al, 2011) (Perdigoto and Bardin, 2013). Preventing JAK/Stat signalling through knock down of Drosophila Hop/JAK, the cytokine receptor Domeless or the transcription factor Stat leads to an overrepresentation of stem/progenitor cells in the adult midgut (Beebe et al, 2010).…”

Section: Basal Homeostatic Self-renewal Of the Adult Drosophila Midgutmentioning

confidence: 99%

Intestinal stem cell proliferation and epithelial homeostasis in the adult Drosophila midgut

Nászai

Carroll

Cordero

2015

Insect Biochemistry and Molecular Biology

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Adult tissue homeostasis requires a tight balance between the removal of old or damaged cells and the production of new ones. Such processes are usually driven by dedicated stem cells that reside within specific tissue locations or niches (Nystul and Spradling, 2006).The intestinal epithelium has a remarkable regenerative capacity, which has made it a prime paradigm for the study of stem cell-driven tissue self-renewal. The discovery of the presence of stem cells in the adult midgut of the fruit fly Drosophila melanogaster has significantly impacted our understanding of the role of stem cells in intestinal homeostasis. Here we will review the current knowledge of the main mechanisms involved in the regulation of tissue homeostasis in the adult Drosophila midgut, with a focus on the role of stem cells in this process. We will also discuss processes involving acute or chronic disruption of normal intestinal homeostasis such as damage-induced regeneration and ageing.3

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Distinct levels of Notch activity for commitment and terminal differentiation of stem cells in the adult fly intestine

Cited by 142 publications

References 63 publications

Rescue of Notch signaling in cells incapable of GDP- l -fucose synthesis by gap junction transfer of GDP- l -fucose in Drosophila

Rescue of Notch signaling in cells incapable of GDP- l -fucose synthesis by gap junction transfer of GDP- l -fucose in Drosophila

Mapping Sites of O-Glycosylation and Fringe Elongation on Drosophila Notch

Intestinal stem cell proliferation and epithelial homeostasis in the adult Drosophila midgut

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