Genome integrity and neurogenesis of postnatal hippocampal neural stem/progenitor cells require a unique regulator Filia

Li, Jingzheng; Shang, Yanfeng; Wang, Lin; Zhao, Bo; Sun, Chunli; Li, Jiali; Liu, Siling; Li, Cong; Tang, Min; Meng, Fei-Long; Zheng, Ping

doi:10.1126/sciadv.aba0682

Cited by 13 publications

(9 citation statements)

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“…NSPCs are the cellular basis for neurogenesis at fetal and postnatal stages. Accumulations of DNA DSBs and cytosolic double-strand DNA (dsDNA) in NSPCs and their progenies not only impaired neurogenesis and brain functions 28 , 29 , but also evoked innate immune and inflammation responses leading to animal death 30 . Based on the function of Discn in in-vitro cultured NSPCs, we hypothesized that Discn KO might cause accumulations of DSBs and cytosolic dsDNA in brain cells of neonates and adults, and the damages and associated immune responses underlie the newborn death and brain dysfunctions.…”

Section: Resultsmentioning

confidence: 99%

“…Many genes critical for neurogenesis in NSPCs harbor RDCs and are susceptible to replication stress-associated perturbations. Thus, replication-associated DNA DSBs in NSPCs directly impacted neurogenesis 29 , 38 , 39 . In addition, DNA DSBs and in particular cytoplasmic dsDNA are able to evoke innate immune response and inflammatory reactions 33 , 40 .…”

Section: Discussionmentioning

confidence: 99%

“…Mouse NSPC was previously derived from WT mice at postnatal day 5 (P5) 29 . Cells were seeded in 35-mm dishes pre-coated with Laminin (Sigma, L2020) and maintained in complete medium (STEMCELL Technologies, 05702) supplemented with 10 ng/mL basic fibroblast growth factor (bFGF) (STEMCELL Technologies, 02634), 20 ng/mL recombinant human epidermal growth factor (rhEGF) (STEMCELL Technologies, 02633), and 2 μg/mL heparin (STEMCELL Technologies, 07980).…”

Section: Methodsmentioning

confidence: 99%

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A novel lncRNA Discn fine-tunes replication protein A (RPA) availability to promote genomic stability

Wang

Zhou

et al. 2021

Nat Commun

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RPA is a master regulator of DNA metabolism and RPA availability acts as a rate-limiting factor. While numerous studies focused on the post-translational regulations of RPA for its functions, little is known regarding how RPA availability is controlled. Here we identify a novel lncRNA Discn as the guardian of RPA availability in stem cells. Discn is induced upon genotoxic stress and binds to neucleolin (NCL) in the nucleolus. This prevents NCL from translocation into nucleoplasm and avoids undesirable NCL-mediated RPA sequestration. Thus, Discn-NCL-RPA pathway preserves a sufficient RPA pool for DNA replication stress response and repair. Discn loss causes massive genome instability in mouse embryonic stem cells and neural stem/progenigor cells. Mice depleted of Discn display newborn death and brain dysfunctions due to DNA damage accumulation and associated inflammatory reactions. Our findings uncover a key regulator of DNA metabolism and provide new clue to understand the chemoresistance in cancer treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A novel lncRNA Discn fine-tunes replication protein A (RPA) availability to promote genomic stability

Wang

Zhou

et al. 2021

Nat Commun

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“…Finally, it was recently demonstrated that regional regulator Filia is required for neurodevelopment. In this study, both murine hippocampus and the NSPCs’ research models were used [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Non-Homologous End Joining Factors XLF, PAXX and DNA-PKcs Maintain the Neural Stem and Progenitor Cell Population

Gago-Fuentes

Oksenych

2020

Biomolecules

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Non-homologous end-joining (NHEJ) is a major DNA repair pathway in mammalian cells that recognizes, processes and fixes DNA damage throughout the cell cycle and is specifically important for homeostasis of post-mitotic neurons and developing lymphocytes. Neuronal apoptosis increases in the mice lacking NHEJ factors Ku70 and Ku80. Inactivation of other NHEJ genes, either Xrcc4 or Lig4, leads to massive neuronal apoptosis in the central nervous system (CNS) that correlates with embryonic lethality in mice. Inactivation of either Paxx, Mri or Dna-pkcs NHEJ gene results in normal CNS development due to compensatory effects of Xlf. Combined inactivation of Xlf/Paxx, Xlf/Mri and Xlf/Dna-pkcs, however, results in late embryonic lethality and high levels of apoptosis in CNS. To determine the impact of NHEJ factors on the early stages of neurodevelopment, we isolated neural stem and progenitor cells from mouse embryos and investigated proliferation, self-renewal and differentiation capacity of these cells lacking either Xlf, Paxx, Dna-pkcs, Xlf/Paxx or Xlf/Dna-pkcs. We found that XRCC4-like factor (XLF), DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and paralogue of XRCC4 and XLF (PAXX) maintain the neural stem and progenitor cell populations and neurodevelopment in mammals, which is particularly evident in the double knockout models.

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“…Germane to HMZ pathology is the production of reactive oxygen species (ROS), which is implicated in oxidative macromolecular damage, inflammatory response, endoplasmic reticulum (ER) stress and apoptosis [18][19][20][21][22]. The developing brain is especially susceptible to genomic instability and cellular stress engendered by oxidative modification of macromolecules and this is also linked to neurodevelopmental and neurodegenerative diseases including Schizophrenia, Alzheimer's (AD) and Parkinson's (PD) diseases [23][24][25][26][27]. Interestingly, reports by Thiam et al…”

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confidence: 99%

Inflammation and Cellular Stress Induced Neurological Sequelae ofPlasmodium falciparumMalaria

Wruck

Adjaye

2021

Preprint

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Background: Malaria caused by Plasmodium falciparum results in severe complications including cerebral malaria (CM) especially in children. While the majority of falciparum malaria survivors make a full recovery, there are reports of some patients ending up with neurological sequelae. Methods: We performed an analysis of pooled transcriptome data of whole blood samples derived from two studies involving various Plasmodium falciparum infections, comprising mild malaria (MM), non-cerebral severe malaria (NCM) and CM. Pathways and gene ontologies (GOs) elevated in the distinct falciparum infections were identified. Results: Contrary to other research findings, our analysis showed MM share similar biological processes with cancer and neurodegenerative diseases, NCM is associated with drug resistance and glutathione metabolism and CM is correlated with endocannabinoid signaling and non-alcoholic fatty liver disease (NAFLD). GO revealed the terms biogenesis, DNA damage response and IL-10 production in MM, down-regulation of cytoskeletal organization and amyloid-beta clearance in NCM and aberrant signaling, neutrophil degranulation and gene repression in CM. Differential gene expression analysis between CM and NCM showed the up-regulation of neutrophil activation and response to herbicides while regulation of axon diameter was down-regulated in CM. Conclusions: The results of this study have demonstrated that the deleterious effect of falciparum malaria on the brain may not be limited to CM and NCM alone but also MM. However, the severity of neurological deficit in CM might be due to the down-regulation of various genes involved in cellular function through transcriptional repression, axonal dysfunction, dysregulation of signaling pathways and neurodegeneration as a result of inflammation and cellular stress. We anticipate that our data might form the basis for future hypothesis-driven malaria research.

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Genome integrity and neurogenesis of postnatal hippocampal neural stem/progenitor cells require a unique regulator Filia

Cited by 13 publications

References 60 publications

A novel lncRNA Discn fine-tunes replication protein A (RPA) availability to promote genomic stability

A novel lncRNA Discn fine-tunes replication protein A (RPA) availability to promote genomic stability

Non-Homologous End Joining Factors XLF, PAXX and DNA-PKcs Maintain the Neural Stem and Progenitor Cell Population

Inflammation and Cellular Stress Induced Neurological Sequelae ofPlasmodium falciparumMalaria

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