Neural stem cell temporal patterning and brain tumour growth rely on oxidative phosphorylation

Ameele, Jelle van den; Brand, Andrea H.

doi:10.7554/elife.47887

Cited by 49 publications

(64 citation statements)

References 88 publications

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“…Neil1 −/− mice that are challenged with ionizing radiation also show behavioral and neurological defects ( 86 ). ROS, which generate the formamidopyrimidines NEIL1 substrates ( 87 ), increase during neurogenesis, a process that is dependent on oxidative phosphorylation ( 88 ). These composite observations support an essential role for NEIL1 and other BER enzymes in the protection of the developing embryo from the harmful effects of endogenous DNA damage, a side effect of tissue differentiation during development.…”

Section: Discussionmentioning

confidence: 99%

Heritable pattern of oxidized DNA base repair coincides with pre-targeting of repair complexes to open chromatin

Bacolla

Sengupta

et al. 2020

Nucleic Acids Research

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Human genome stability requires efficient repair of oxidized bases, which is initiated via damage recognition and excision by NEIL1 and other base excision repair (BER) pathway DNA glycosylases (DGs). However, the biological mechanisms underlying detection of damaged bases among the million-fold excess of undamaged bases remain enigmatic. Indeed, mutation rates vary greatly within individual genomes, and lesion recognition by purified DGs in the chromatin context is inefficient. Employing super-resolution microscopy and co-immunoprecipitation assays, we find that acetylated NEIL1 (AcNEIL1), but not its non-acetylated form, is predominantly localized in the nucleus in association with epigenetic marks of uncondensed chromatin. Furthermore, chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) revealed non-random AcNEIL1 binding near transcription start sites of weakly transcribed genes and along highly transcribed chromatin domains. Bioinformatic analyses revealed a striking correspondence between AcNEIL1 occupancy along the genome and mutation rates, with AcNEIL1-occupied sites exhibiting fewer mutations compared to AcNEIL1-free domains, both in cancer genomes and in population variation. Intriguingly, from the evolutionarily conserved unstructured domain that targets NEIL1 to open chromatin, its damage surveillance of highly oxidation-susceptible sites to preserve essential gene function and to limit instability and cancer likely originated ∼500 million years ago during the buildup of free atmospheric oxygen.

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Section: Discussionmentioning

confidence: 99%

Heritable pattern of oxidized DNA base repair coincides with pre-targeting of repair complexes to open chromatin

Bacolla

Sengupta

et al. 2020

Nucleic Acids Research

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“…However, ATP depletion has been reported only on combined loss of oxidative phosphorylation and glycolysis and brat RNAi driven tumors rely on NAD+ metabolism rather than ATP synthesis [22][23][24]. Since we did not see any [23] and it will be interesting to probe if fusion of mitochondria in ETC mutants will also mitigate the differentiation defect.…”

Section: Role Of Mitochondrial Fusion In Notch Driven Differentiationmentioning

confidence: 77%

“…To check whether ATP stress was seen in mitochondrial fusion mutant NBs, we stained brains with antibodies against pAMPK. NB differentiation relies at least in part on glycolytic metabolism for ATP and loss of ATP in ETC mutants is seen when depleted of both glycolysis and ETC activity [22,23]. Therefore as a positive control for reduction in glycolysis and induction of pAMPK we added 2-deoxy-glucose (2-DG), a non-hydrolysable analogue of glucose to larval brains after dissection and observed a significant increase in pAMPK levels throughout the brain.…”

Section: Decrease In Mitochondrial Activity In Opa1 and Marf Depletedmentioning

confidence: 99%

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Mitochondrial fusion regulates proliferation and differentiation in the type II neuroblast lineage inDrosophila

Dubal

Moghe

Uttekar

et al. 2021

Preprint

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Optimal mitochondrial function determined by mitochondrial dynamics, morphology and activity is coupled to stem cell differentiation and organism development. However, the mechanisms of interaction of signaling pathways with mitochondrial morphology and activity are not completely understood. We assessed the role of mitochondrial fusion and fission in differentiation of neural stem cells called neuroblasts (NB) in the Drosophila brain. Depletion of mitochondrial inner membrane fusion protein Opa1 and mitochondrial outer membrane protein Marf in the Drosophila type II neuroblast lineage led to mitochondrial fragmentation and loss of activity. Opa1 and Marf depletion did not affect the numbers and polarity of type II neuroblasts but led to a decrease in proliferation and differentiation of cells in the lineage. On the contrary, loss of mitochondrial fission protein Drp1 led to mitochondrial fusion but did not show defects in proliferation and differentiation. Depletion of Drp1 along with Opa1 or Marf also led to mitochondrial fusion and suppressed fragmentation, loss of mitochondrial activity, proliferation and differentiation in the type II NB lineage. We found that Notch signaling depletion via the canonical pathway showed mitochondrial fragmentation and loss of differentiation similar to Opa1 mutants. An increase in Notch signaling required mitochondrial fusion for NB proliferation. Further, Drp1 mutants in combination with Notch depletion showed mitochondrial fusion and drove differentiation in the lineage suggesting that fused mitochondria can influence Notch signaling driven differentiation in the type II NB lineage. Our results implicate a crosstalk between Notch signalling, mitochondrial activity and mitochondrial fusion as an essential step in type II NB differentiation.

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“…1 ) ( Abdusselamoglu et al, 2019 ; Averbukh et al, 2018 ; Grosskortenhaus et al, 2005 ). Some temporal transitions appear to require cell-cycle progression or high levels of oxidative phosphorylation ( Grosskortenhaus et al, 2005 ; van den Ameele and Brand, 2019 ). Although temporal patterning progression in most NBs appears to be mainly intrinsically driven, external cues, such as the steroid hormone ecdysone, may also facilitate temporal transitions, especially in type II NBs ( Fig.…”

Section: Temporal Patterning: a Versatile System To Coordinate Cell Fmentioning

confidence: 99%

Temporal patterning in neural progenitors: from Drosophila development to childhood cancers

Maurange

2020

Disease Models &Amp; Mechanisms

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The developing central nervous system (CNS) is particularly prone to malignant transformation, but the underlying mechanisms remain unresolved. However, periods of tumor susceptibility appear to correlate with windows of increased proliferation, which are often observed during embryonic and fetal stages and reflect stereotypical changes in the proliferative properties of neural progenitors. The temporal mechanisms underlying these proliferation patterns are still unclear in mammals. In Drosophila, two decades of work have revealed a network of sequentially expressed transcription factors and RNA-binding proteins that compose a neural progenitor-intrinsic temporal patterning system. Temporal patterning controls both the identity of the post-mitotic progeny of neural progenitors, according to the order in which they arose, and the proliferative properties of neural progenitors along development. In addition, in Drosophila, temporal patterning delineates early windows of cancer susceptibility and is aberrantly regulated in developmental tumors to govern cellular hierarchy as well as the metabolic and proliferative heterogeneity of tumor cells. Whereas recent studies have shown that similar genetic programs unfold during both fetal development and pediatric brain tumors, I discuss, in this Review, how the concept of temporal patterning that was pioneered in Drosophila could help to understand the mechanisms of initiation and progression of CNS tumors in children.

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Neural stem cell temporal patterning and brain tumour growth rely on oxidative phosphorylation

Cited by 49 publications

References 88 publications

Heritable pattern of oxidized DNA base repair coincides with pre-targeting of repair complexes to open chromatin

Heritable pattern of oxidized DNA base repair coincides with pre-targeting of repair complexes to open chromatin

Mitochondrial fusion regulates proliferation and differentiation in the type II neuroblast lineage inDrosophila

Temporal patterning in neural progenitors: from Drosophila development to childhood cancers

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