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Aneuploidy causes premature differentiation of neural and intestinal stem cells.

Gogendeau D, Siudeja K, Gambarotto D, Pennetier C, Bardin AJ, Basto R - Nat Commun (2015)

Bottom Line: We show that aneuploidy causes brain size reduction due to a decrease in the number of proliferative neural stem cells (NSCs), but not through apoptosis.Moreover, we show that this response to aneuploidy is also present in adult intestinal stem cells but not in the wing disc.Our work highlights a neural and intestine stem cell-specific response to aneuploidy, which prevents their proliferation and expansion.

View Article: PubMed Central - PubMed

Affiliation: Institut Curie, PSL Research University, CNRS UMR144, 12 rue Lhomond, Paris 75005, France.

ABSTRACT
Aneuploidy is associated with a variety of diseases such as cancer and microcephaly. Although many studies have addressed the consequences of a non-euploid genome in cells, little is known about their overall consequences in tissue and organism development. Here we use two different mutant conditions to address the consequences of aneuploidy during tissue development and homeostasis in Drosophila. We show that aneuploidy causes brain size reduction due to a decrease in the number of proliferative neural stem cells (NSCs), but not through apoptosis. Instead, aneuploid NSCs present an extended G1 phase, which leads to cell cycle exit and premature differentiation. Moreover, we show that this response to aneuploidy is also present in adult intestinal stem cells but not in the wing disc. Our work highlights a neural and intestine stem cell-specific response to aneuploidy, which prevents their proliferation and expansion.

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Aneuploid brains have reduced tumorigenic capacity.(a). Pictures of WT adult host flies transplanted with Tubulin-GFP (left) or Tubulin-GFP; SakOE,mad2 (right) pieces of L3 brains. Scale bars, 400 μm. (b) Graph bars showing the quantification of tumour formation for indicated genotypes. Numbers on top of each column indicate the number of transplants performed. Statistical significance was determined using Fet *(P=0.03). (c) Immunostaining of WT, SakOE,mad2 and bub3 L3 Nbs with α-tubulin (left and in red in the merged panel), dPLP (Drosophila pericentrin-like protein) and aPKC (middle panel, shown in green in the merged panel) antibodies. DNA is shown in blue. Scale bar, 2 μm. (d) Quantification of mitotic spindle orientation at anaphase in WT (n=24), SakOE, mad2 (n=45) and bub3 (n=24). Only SakOE,mad2 Nbs present spindle position defects. Statistical significance was determined using unpaired t-test ****(P<0.0001).
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f7: Aneuploid brains have reduced tumorigenic capacity.(a). Pictures of WT adult host flies transplanted with Tubulin-GFP (left) or Tubulin-GFP; SakOE,mad2 (right) pieces of L3 brains. Scale bars, 400 μm. (b) Graph bars showing the quantification of tumour formation for indicated genotypes. Numbers on top of each column indicate the number of transplants performed. Statistical significance was determined using Fet *(P=0.03). (c) Immunostaining of WT, SakOE,mad2 and bub3 L3 Nbs with α-tubulin (left and in red in the merged panel), dPLP (Drosophila pericentrin-like protein) and aPKC (middle panel, shown in green in the merged panel) antibodies. DNA is shown in blue. Scale bar, 2 μm. (d) Quantification of mitotic spindle orientation at anaphase in WT (n=24), SakOE, mad2 (n=45) and bub3 (n=24). Only SakOE,mad2 Nbs present spindle position defects. Statistical significance was determined using unpaired t-test ****(P<0.0001).

Mentions: Aneuploidy can be seen as tumour suppressor or oncogenic1656. SakOE brains induced tumour formation, due to spindle positioning defects, which resulted in the expansion of the Nbs pool12. We wondered whether the addition of aneuploidy to a tumour-permissive condition would influence the tumourigenic capacity of SakOE Nbs by transplanting SakOE,mad2 brain pieces into the abdomen of WT hosts. Interestingly, we found a clear decrease in the tumourigenic potential of SakOE,mad2 brains (Fig. 7a,b). Nevertheless, these brains were still tumourigenic, while other aneuploid mutants such as bub3 (ref. 11) were not.


Aneuploidy causes premature differentiation of neural and intestinal stem cells.

Gogendeau D, Siudeja K, Gambarotto D, Pennetier C, Bardin AJ, Basto R - Nat Commun (2015)

Aneuploid brains have reduced tumorigenic capacity.(a). Pictures of WT adult host flies transplanted with Tubulin-GFP (left) or Tubulin-GFP; SakOE,mad2 (right) pieces of L3 brains. Scale bars, 400 μm. (b) Graph bars showing the quantification of tumour formation for indicated genotypes. Numbers on top of each column indicate the number of transplants performed. Statistical significance was determined using Fet *(P=0.03). (c) Immunostaining of WT, SakOE,mad2 and bub3 L3 Nbs with α-tubulin (left and in red in the merged panel), dPLP (Drosophila pericentrin-like protein) and aPKC (middle panel, shown in green in the merged panel) antibodies. DNA is shown in blue. Scale bar, 2 μm. (d) Quantification of mitotic spindle orientation at anaphase in WT (n=24), SakOE, mad2 (n=45) and bub3 (n=24). Only SakOE,mad2 Nbs present spindle position defects. Statistical significance was determined using unpaired t-test ****(P<0.0001).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4660207&req=5

f7: Aneuploid brains have reduced tumorigenic capacity.(a). Pictures of WT adult host flies transplanted with Tubulin-GFP (left) or Tubulin-GFP; SakOE,mad2 (right) pieces of L3 brains. Scale bars, 400 μm. (b) Graph bars showing the quantification of tumour formation for indicated genotypes. Numbers on top of each column indicate the number of transplants performed. Statistical significance was determined using Fet *(P=0.03). (c) Immunostaining of WT, SakOE,mad2 and bub3 L3 Nbs with α-tubulin (left and in red in the merged panel), dPLP (Drosophila pericentrin-like protein) and aPKC (middle panel, shown in green in the merged panel) antibodies. DNA is shown in blue. Scale bar, 2 μm. (d) Quantification of mitotic spindle orientation at anaphase in WT (n=24), SakOE, mad2 (n=45) and bub3 (n=24). Only SakOE,mad2 Nbs present spindle position defects. Statistical significance was determined using unpaired t-test ****(P<0.0001).
Mentions: Aneuploidy can be seen as tumour suppressor or oncogenic1656. SakOE brains induced tumour formation, due to spindle positioning defects, which resulted in the expansion of the Nbs pool12. We wondered whether the addition of aneuploidy to a tumour-permissive condition would influence the tumourigenic capacity of SakOE Nbs by transplanting SakOE,mad2 brain pieces into the abdomen of WT hosts. Interestingly, we found a clear decrease in the tumourigenic potential of SakOE,mad2 brains (Fig. 7a,b). Nevertheless, these brains were still tumourigenic, while other aneuploid mutants such as bub3 (ref. 11) were not.

Bottom Line: We show that aneuploidy causes brain size reduction due to a decrease in the number of proliferative neural stem cells (NSCs), but not through apoptosis.Moreover, we show that this response to aneuploidy is also present in adult intestinal stem cells but not in the wing disc.Our work highlights a neural and intestine stem cell-specific response to aneuploidy, which prevents their proliferation and expansion.

View Article: PubMed Central - PubMed

Affiliation: Institut Curie, PSL Research University, CNRS UMR144, 12 rue Lhomond, Paris 75005, France.

ABSTRACT
Aneuploidy is associated with a variety of diseases such as cancer and microcephaly. Although many studies have addressed the consequences of a non-euploid genome in cells, little is known about their overall consequences in tissue and organism development. Here we use two different mutant conditions to address the consequences of aneuploidy during tissue development and homeostasis in Drosophila. We show that aneuploidy causes brain size reduction due to a decrease in the number of proliferative neural stem cells (NSCs), but not through apoptosis. Instead, aneuploid NSCs present an extended G1 phase, which leads to cell cycle exit and premature differentiation. Moreover, we show that this response to aneuploidy is also present in adult intestinal stem cells but not in the wing disc. Our work highlights a neural and intestine stem cell-specific response to aneuploidy, which prevents their proliferation and expansion.

Show MeSH
Related in: MedlinePlus