Transmembrane Protein 18 Enhances the Tropism of Neural Stem Cells for Glioma Cells

Glioblastoma multiforme (GBM) is the most aggressive human primary brain cancer. Using a Trp53-deficient mouse model of GBM, we show that genetic inactivation of the Atm cofactor Atmin, which is dispensable for embryonic and adult neural development, strongly suppresses GBM formation. Mechanistically, expression of several GBM-associated genes, including Pdgfra, was normalized by Atmin deletion in the Trp53-null background. Pharmacological ATM inhibition also reduced Pdgfra expression, and reduced the proliferation of Trp53-deficient primary glioma cells from murine and human tumors, while normal neural stem cells were unaffected. Analysis of GBM datasets showed that PDGFRA expression is also significantly increased in human TP53-mutant compared with TP53-wild-type tumors. Moreover, combined treatment with ATM and PDGFRA inhibitors efficiently killed TP53-mutant primary human GBM cells, but not untransformed neural stem cells. These results reveal a new requirement for ATMIN-dependent ATM signaling in TP53-deficient GBM, indicating a pro-tumorigenic role for ATM in the context of these tumors.

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MAP Kinase Signaling Differences between Neural Stem Cells and Glioma Cells Provide a Mechanism for Selective Neuroprotection During Cranial Irradiation

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2014.05.621 ◽

2014 ◽

Vol 90 (1) ◽

pp. S148

Author(s):

A. Stessin ◽

M. Banu ◽

J.A. Boockvar ◽

B. Parashar ◽

A.G. Wernicke ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Map Kinase ◽

Glioma Cells ◽

Cranial Irradiation ◽

Kinase Signaling ◽

Map Kinase Signaling

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Reciprocal effects of conditioned medium on cultured glioma cells and neural stem cells

Journal of Clinical Neuroscience ◽

10.1016/j.jocn.2009.04.009 ◽

2009 ◽

Vol 16 (12) ◽

pp. 1619-1623 ◽

Cited By ~ 6

Author(s):

Fu Xue Chen ◽

Wen Wen Ren ◽

Yang Yang ◽

Di Shen ◽

Yijia Zong ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Conditioned Medium ◽

Glioma Cells ◽

Reciprocal Effects

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Transmembrane Protein Ttyh1 Maintains the Quiescence of Neural Stem Cells Through Ca2+/NFATc3 Signaling

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.779373 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yuan Cao ◽

Hai-ning Wu ◽

Xiu-li Cao ◽

Kang-yi Yue ◽

Wen-juan Han ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Transmembrane Protein ◽

Spatial Learning And Memory ◽

Specific Expression ◽

Adult Mice ◽

Molecular Biological Analysis ◽

Reporter Mice ◽

Physiological Homeostasis

The quiescence, activation, and subsequent neurogenesis of neural stem cells (NSCs) play essential roles in the physiological homeostasis and pathological repair of the central nervous system. Previous studies indicate that transmembrane protein Ttyh1 is required for the stemness of NSCs, whereas the exact functions in vivo and precise mechanisms are still waiting to be elucidated. By constructing Ttyh1-promoter driven reporter mice, we determined the specific expression of Ttyh1 in quiescent NSCs and niche astrocytes. Further evaluations on Ttyh1 knockout mice revealed that Ttyh1 ablation leads to activated neurogenesis and enhanced spatial learning and memory in adult mice (6–8 weeks). Correspondingly, Ttyh1 deficiency results in accelerated exhaustion of NSC pool and impaired neurogenesis in aged mice (12 months). By RNA-sequencing, bioinformatics and molecular biological analysis, we found that Ttyh1 is involved in the regulation of calcium signaling in NSCs, and transcription factor NFATc3 is a critical effector in quiescence versus cell cycle entry regulated by Ttyh1. Our research uncovered new endogenous mechanisms that regulate quiescence versus activation of NSCs, therefore provide novel targets for the intervention to activate quiescent NSCs to participate in injury repair during pathology and aging.

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Meta-analysis of whole-genome gene expression datasets assessing the effects of IDH1 and IDH2 mutations in isogenic disease models

Scientific Reports ◽

10.1038/s41598-021-04214-7 ◽

2022 ◽

Vol 12 (1) ◽

Author(s):

Hans-Juergen Schulten ◽

Fatima Al-Adwani ◽

Haneen A. Bin Saddeq ◽

Heba Alkhatabi ◽

Nofe Alganmi ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Expression Profiles ◽

Meta Analysis ◽

Glioma Cells ◽

Heart Tissue ◽

Disease Models ◽

Signal Molecules ◽

Mouse Heart ◽

Idh Mutations

AbstractMutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are oncogenic drivers to a variable extent in several tumors, including gliomas, acute myeloid leukemia (AML), cholangiocarcinoma, melanoma, and thyroid carcinoma. The pathobiological effects of these mutations vary considerably, impeding the identification of common expression profiles. We performed an expression meta-analysis between IDH-mutant (IDHmut) and IDH-wild-type (IDHwt) conditions in six human and mouse isogenic disease models. The datasets included colon cancer cells, glioma cells, heart tissue, hepatoblasts, and neural stem cells. Among differentially expressed genes (DEGs), serine protease 23 (PRSS23) was upregulated in four datasets, i.e., in human colon carcinoma cells, mouse heart tissue, mouse neural stem cells, and human glioma cells. Carbonic anhydrase 2 (CA2) and prolyl 3-hydroxylase 2 (P3H2) were upregulated in three datasets, and SOX2 overlapping transcript (SOX2-OT) was downregulated in three datasets. The most significantly overrepresented protein class was termed intercellular signal molecules. An additional DEG set contained genes that were both up- and downregulated in different datasets and included oxidases and extracellular matrix structural proteins as the most significantly overrepresented protein classes. In conclusion, this meta-analysis provides a comprehensive overview of the expression effects of IDH mutations shared between different isogenic disease models. The generated dataset includes biomarkers, e.g., PRSS23 that may gain relevance for further research or clinical applications in IDHmut tumors.

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Regenerative neurogenic response from glia requires insulin driven neuron-glia communication

10.1101/721498 ◽

2019 ◽

Author(s):

Neale Harrison ◽

Elizabeth Connolly ◽

Alicia Gascón Gubieda ◽

Zidan Yang ◽

Benjamin Altenhein ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Cell Fate ◽

Glial Cells ◽

De Novo ◽

Transmembrane Protein ◽

Lineage Tracing ◽

Epistasis Analysis ◽

Induced Neural Stem Cell ◽

Underlying Mechanisms

ABSTRACTSome animals can regenerate their central nervous system (CNS) after injury by inducing de novo neurogenesis: discovering the underlying mechanisms would help promote regeneration in the damaged human CNS. Glial cells could be the source of regenerative neurogenesis, but this is debated. The glia transmembrane protein Neuron-Glia antigen-2 (NG2) may have a key role in sensing injury-induced neuronal signals, however these have not been identified. Here, we used Drosophila genetics to search for functional neuronal partners of the NG2 homologue kon-tiki (kon), and identified Islet Antigen-2 (Ia-2), required in neurons for insulin secretion. Alterations in Ia-2 function induced neural stem cell fate, injury increased ia-2 expression and induced ectopic neural stem cells. Using genetic epistasis analysis and lineage tracing, we demonstrate that Ia-2 functions with Kon to regulate Drosophila insulin-like peptide 6 (Dilp-6) which in turn generates both more glial cells and neural stem cells from glia. Ectopic neural stem cells can divide, and limited de novo neurogenesis could be traced back to glial cells. Altogether, Ia-2 and Dilp-6 drive a neuron-glia relay that restores glia, and reprograms glia into neural stem cells for CNS regeneration.

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