FOS Rescues Neuronal Differentiation of Sox2-Deleted Neural Stem Cells by Genome-Wide Regulation of Common SOX2 and AP1(FOS-JUN) Target Genes

The transcription factor SOX2 is important for brain development and for neural stem cells (NSC) maintenance. Sox2-deleted (Sox2-del) NSC from neonatal mouse brain are lost after few passages in culture. Two highly expressed genes, Fos and Socs3, are strongly downregulated in Sox2-del NSC; we previously showed that Fos or Socs3 overexpression by lentiviral transduction fully rescues NSC’s long-term maintenance in culture. Sox2-del NSC are severely defective in neuronal production when induced to differentiate. NSC rescued by Sox2 reintroduction correctly differentiate into neurons. Similarly, Fos transduction rescues normal or even increased numbers of immature neurons expressing beta-tubulinIII, but not more differentiated markers (MAP2). Additionally, many cells with both beta-tubulinIII and GFAP expression appear, indicating that FOS stimulates the initial differentiation of a “mixed” neuronal/glial progenitor. The unexpected rescue by FOS suggested that FOS, a SOX2 transcriptional target, might act on neuronal genes, together with SOX2. CUT&RUN analysis to detect genome-wide binding of SOX2, FOS, and JUN (the AP1 complex) revealed that a high proportion of genes expressed in NSC are bound by both SOX2 and AP1. Downregulated genes in Sox2-del NSC are highly enriched in genes that are also expressed in neurons, and a high proportion of the “neuronal” genes are bound by both SOX2 and AP1.

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Betamethasone Induces a Unique Transcriptome in Neural Stem Cells

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1631 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A802-A802

Author(s):

Neerupma Silswal ◽

Joe Bean ◽

Herschel Gupta ◽

Fatma Talib ◽

Suban Burale ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Serotonin Receptor ◽

Target Genes ◽

Biological Response ◽

The United States ◽

Oligodendrocyte Differentiation

Abstract Twelve percent of pregnant women receive glucocorticoids (sGCs) to reduce the risks to reduce morbidity and mortality associated with preterm birth in infants. The two most commonly administered sGC are Dexamethasone (Dex) and Betamethasone (Beta) and they serve to decrease the severity of respiratory distress, intraventricular hemorrhage and necrotizing enterocolitis. However, repeated administration of sGC has been shown to be associated with adverse neurological outcome and depends on the type of sGCs used, dose, timing of sGCs administration and sex. We have previously shown that prenatal exposure to Dex in a murine model lead to sex specific changes in the transcription response and in the biological function of neural stem cells and to long-term changes in brain architecture and behavior. Beta is the predominant sGC used prenatally in the United States, therefore these studies investigated the cellular and molecular responses to beta exposure on the neural stem cells in-vitro and anatomical organization of the brain in-vivo. Murine NSCs were isolated from the E14.5 cerebral cortex and exposed to 10-7 M Dex, 10-7 M Beta, or Vehicle for 4 or 24 hours and the immediate and long-term impact on transcription, proliferation and neuronal, glial and oligodendrocyte differentiation examined. Affymetrix genome transcriptional analyses reveal sex specific responses to Dex vs Beta in 4 hours. In females 682 genes were differentially regulated by Dex compared to 576 by Beta. In contrast, 875 were altered by Dex and 576 by Beta in males (Fold change > +/- 1.5, P< 0.05). Select target genes were independently validated by QPCR. Ingenuity Pathway Analysis was used to identify unique and overlapping pathways that were altered by Dex vs Beta. In males, Dex uniquely altered 34 pathways including, Thyroid Hormone Metabolism, ERK5 Signaling and Opioid Signaling while Bata altered 33 pathways including, Phagasome formation, IL-7 Signaling and JAK STAT signaling. In Females, Dex altered 45 pathways including Calcium Signaling, Serotonin Receptor Signaling and Xenobiotic Signaling, while Beta altered 46 pathways including, FXR/RXR Activation, Tec Kinase Signaling and D-myo-Inositol-5-Phosphate Metabolism. Another 35 pathways were altered by both Dex and Beta but they showed differences in genes activated or repressed. Dex and Beta, both significantly altered genes involved in proliferation and differentiation therefore the biological response of NSC to sGCs stimulation in vitro and the long term consequences of sGC exposure in-vivo was compared. Distinct differences in cell proliferation, glial and oligodendrocyte differentiation were observed. These results reveal gene targets, cellular pathways and processes that are differentially altered by prenatal Dex vs Beta exposure. Our finds may provide insights into the sex specific neurological outcomes observed in children exposed to sGCs in-utero.

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Faculty Opinions recommendation of Lineage hierarchies and stochasticity ensure the long-term maintenance of adult neural stem cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.737901162.793574455 ◽

2020 ◽

Author(s):

Caghan Kizil

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Adult Neural Stem Cells ◽

Term Maintenance

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RBPJ -Dependent Signaling Is Essential for Long-Term Maintenance of Neural Stem Cells in the Adult Hippocampus

Journal of Neuroscience ◽

10.1523/jneurosci.1567-10.2010 ◽

2010 ◽

Vol 30 (41) ◽

pp. 13794-13807 ◽

Cited By ~ 193

Author(s):

O. Ehm ◽

C. Goritz ◽

M. Covic ◽

I. Schaffner ◽

T. J. Schwarz ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Adult Hippocampus ◽

Term Maintenance

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Ganglioside GD3 Is Required for Neurogenesis and Long-Term Maintenance of Neural Stem Cells in the Postnatal Mouse Brain

Journal of Neuroscience ◽

10.1523/jneurosci.2275-14.2014 ◽

2014 ◽

Vol 34 (41) ◽

pp. 13790-13800 ◽

Cited By ~ 33

Author(s):

Jing Wang ◽

Allison Cheng ◽

Chandramohan Wakade ◽

Robert K. Yu

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Mouse Brain ◽

Ganglioside Gd3 ◽

Term Maintenance

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BCOR Internal Tandem Duplication Expression in Neural Stem Cells Promotes Growth, Invasion, and Expression of PRC2 Targets

International Journal of Molecular Sciences ◽

10.3390/ijms22083913 ◽

2021 ◽

Vol 22 (8) ◽

pp. 3913

Author(s):

Satoshi Nakata ◽

Ming Yuan ◽

Jeffrey A. Rubens ◽

Ulf D. Kahlert ◽

Jarek Maciaczyk ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Tandem Duplication ◽

Target Genes ◽

Cellular Growth ◽

Central Nervous System Tumor ◽

Internal Tandem Duplication ◽

Invasion And Migration ◽

Human Neural Stem Cells ◽

And Migration

Central nervous system tumor with BCL6-corepressor internal tandem duplication (CNS-BCOR ITD) is a malignant entity characterized by recurrent alterations in exon 15 encoding the essential binding domain for the polycomb repressive complex (PRC). In contrast to deletion or truncating mutations seen in other tumors, BCOR expression is upregulated in CNS-BCOR ITD, and a distinct oncogenic mechanism has been suggested. However, the effects of this change on the biology of neuroepithelial cells is poorly understood. In this study, we introduced either wildtype BCOR or BCOR-ITD into human and murine neural stem cells and analyzed them with quantitative RT-PCR and RNA-sequencing, as well as growth, clonogenicity, and invasion assays. In human cells, BCOR-ITD promoted derepression of PRC2-target genes compared to wildtype BCOR. A similar effect was found in clinical specimens from previous studies. However, no growth advantage was seen in the human neural stem cells expressing BCOR-ITD, and long-term models could not be established. In the murine cells, both wildtype BCOR and BCOR-ITD overexpression affected cellular differentiation and histone methylation, but only BCOR-ITD increased cellular growth, invasion, and migration. BCOR-ITD overexpression drives transcriptional changes, possibly due to altered PRC function, and contributes to the oncogenic transformation of neural precursors.

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