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GSE19240
Homo sapiens
6 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Complete identification of the bone marrow niche remains one of the most progressing fields. Attempts to identify soluble factors involved in stem cell renewal have been less successful. We have previously shown that endothelial cells (EC) can induce the long-term proliferation of hematopoietic progenitor cells (HPC), especially when they had been subjected to an inflammatory stimulus like interleukins (IL) 1.
Publication Title
Interleukin 32 promotes hematopoietic progenitor expansion and attenuates bone marrow cytotoxicity.
Sample Metadata Fields
Specimen part, Treatment, Time
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The choroid plexuses (ChPs) are the main regulators of cerebrospinal fluid (CSF) composition and thereby also control the composition of a principal source of signaling molecules that is in direct contact with neural stem cells in the developing brain. The regulators of ChP development mediating the acquisition of a fate that differs from the neighboring neuroepithelial cells are poorly understood. Here, we demonstrate in mice a crucial role for the transcription factor Otx2 in the development and maintenance of ChP cells. Deletion of Otx2 by the Otx2-CreERT2 driver line at E9 resulted in a lack of all ChPs, whereas deletion by the Gdf7-Cre driver line affected predominately the hindbrain ChP, which was reduced in size, primarily owing to an increase in apoptosis upon Otx2 deletion. Strikingly, Otx2 was still required for the maintenance of hindbrain ChP cells at later stages when Otx2 deletion was induced at E15, demonstrating a central role of Otx2 in ChP development and maintenance. Moreover, the predominant defects in the hindbrain ChP mediated by Gdf7-Cre deletion of Otx2 revealed its key role in regulating early CSF composition, which was altered in protein content, including the levels of Wnt4 and the Wnt modulator Tgm2. Accordingly, proliferation and Wnt signaling levels were increased in the distant cerebral cortex, suggesting a role of the hindbrain ChP in regulating CSF composition, including key signaling molecules. Thus, Otx2 acts as a master regulator of ChP development, thereby influencing one of the principal sources of signaling in the developing brain, the CSF.
Publication Title
The transcription factor Otx2 regulates choroid plexus development and function.
Sample Metadata Fields
Sex
View Samples- Mus musculus
- 13 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Hematopoietic stem cell (HSC) are regulated by their niche, which limits activation of HSCs, to ensure their maintenance and self-renewal.
Publication Title
Stroma-Derived Connective Tissue Growth Factor Maintains Cell Cycle Progression and Repopulation Activity of Hematopoietic Stem Cells In Vitro.
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 6 Downloadable Samples
Illumina HiSeq 1500
Description
In order to understand if early epigenetic mechanisms instruct the long-term behaviour of neural stem cells (NSCs) and their progeny, we examined the protein Uhrf1 as it is highly expressed in NSCs of the developing brain and rapidly downregulated upon differentiation. Conditional deletion of Uhrf1 in the developing cerebral cortex resulted in rather normal proliferation and neurogenesis but severe postnatal neurodegeneration. During development, deletion of Uhrf1 resulted in global DNA hypomethylation with a strong activation of the IAP family of endogenous retroviral elements, accompanied by an increase in hydroxy methyl cytosine. Downregulation of Tet enzymes rescued the IAP activation in Uhrf1 cKO cells, suggesting an antagonistic interplay between Uhrf1 and Tet on IAP regulation. As IAP upregulation persists into postnatal stages in the conditional Uhrf1 KO mice, our data show the lack of means to repress IAPs in differentiating neurons that normally never express Uhrf1. The high load of viral proteins and other transcriptional dysregulation ultimately lead to extensive postnatal neurodegeneration. Taken together, these data show that early developmental NSC factors can have long-term effects in neuronal differentiation and survival. Moreover, it highlights how specific the consequences of widespread changes in DNA methylation are for certain classes of retroviral elements. Overall design: Transcriptome analysis in control vs. Uhrf1-deficient brain
Publication Title
Loss of Uhrf1 in neural stem cells leads to activation of retroviral elements and delayed neurodegeneration.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 5 Downloadable Samples
- Illumina HiSeq 1500
Description
In order to understand if early epigenetic mechanisms instruct the long-term behaviour of neural stem cells (NSCs) and their progeny, we examined the protein Uhrf1 as it is highly expressed in NSCs of the developing brain and rapidly downregulated upon differentiation. Conditional deletion of Uhrf1 in the developing cerebral cortex resulted in rather normal proliferation and neurogenesis but severe postnatal neurodegeneration. During development, deletion of Uhrf1 resulted in global DNA hypomethylation with a strong activation of the IAP family of endogenous retroviral elements, accompanied by an increase in hydroxy methyl cytosine. Downregulation of Tet enzymes rescued the IAP activation in Uhrf1 cKO cells, suggesting an antagonistic interplay between Uhrf1 and Tet on IAP regulation. As IAP upregulation persists into postnatal stages in the conditional Uhrf1 KO mice, our data show the lack of means to repress IAPs in differentiating neurons that normally never express Uhrf1. The high load of viral proteins and other transcriptional dysregulation ultimately lead to extensive postnatal neurodegeneration. Taken together, these data show that early developmental NSC factors can have long-term effects in neuronal differentiation and survival. Moreover, it highlights how specific the consequences of widespread changes in DNA methylation are for certain classes of retroviral elements. Overall design: Transcriptome analysis in control vs. Uhrf1-deficient brain
Publication Title
Loss of Uhrf1 in neural stem cells leads to activation of retroviral elements and delayed neurodegeneration.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 32 Downloadable Samples
- Illumina HiSeq 1500
Description
Mesenchymal stromal cells (MSC) are crucial components of the bone marrow (BM) microenvironment essential for regulating self-renewal, survival and differentiation of hematopoietic stem/progenitor cells (HSPC) in the stem cell niche. MSC are functionally and phenotypically altered in myelodysplastic syndromes (MDS), contributing to disease progression. MDS MSC do not harbor recurrent genetic alterations but have been shown to exhibit an altered methylome compared to MSC from healthy controls. We examined growth, differentiation and HSPC-supporting capacity of ex vivo expanded MSC from MDS patients in comparison to age-matched healthy controls after direct treatment in vitro with the hypomethylating agent azacitidine (AZA). We show that AZA exerts a direct effect on MSC by modulating their differentiation potential. Osteogenesis was significantly boosted in healthy MSC while adipogenesis was inhibited in both healthy and MDS MSC. In co-culture experiments, both AZA treated MDS MSC and healthy MSC exhibited enhanced support of non-clonal HSPC which was associated with increased cell cycle induction. Conversely, clonal MDS HSPC were inhibited by contact with AZA treated MSC. RNA-sequencing analyses of stromal cells revealed changes in pathways essential for HSPC support as well as in immune regulatory pathways. In sum, our data demonstrate that AZA treatment of stromal cells leads to upregulation of HSPC-supportive genes and cell cycle induction in co-cultured healthy HSPC, resulting in a proliferative advantage over clonal HSPC. Thus, restoration of functional hematopoiesis by AZA may be driven by activated stromal support factors in MSC providing cell cycle cues to healthy HSPC. Overall design: RNA sequencing was performed on a mesenchymal stromal cell line (EL08-1D2), either untreated or treated with Azacitidine [(-)AZA vs. (+)AZA].
Publication Title
Direct modulation of the bone marrow mesenchymal stromal cell compartment by azacitidine enhances healthy hematopoiesis.
Sample Metadata Fields
Treatment, Subject
View Samples- Mus musculus
- 20 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The transcription factor Pax6 acts as a key developmental regulator in various organs. In the developing brain Pax6 regulates patterning, neurogenesis and proliferation, but how these diverse effects are mediated at the molecular level is not well understood. As Pax6 regulates forebrain development including neurogenesis, proliferation and patterning, almost exclusively by one of its DNA-binding domains, the bipartite paired domain, we examined the role of its respective DNA-binding subdomains (PAI and RED). Using mice with point mutations in the PAI (Pax6Leca4, N50K) and RED (Pax6Leca2, R128C) subdomains we unravelled opposing roles of mutations in these subdomains in regulating genes that control proliferation in the developing cerebral cortex.
Publication Title
Functional dissection of the paired domain of Pax6 reveals molecular mechanisms of coordinating neurogenesis and proliferation.
Sample Metadata Fields
Sex
View Samples- Mus musculus
- 34 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Reprogramming offers the possibility to study cell fate acquisitions otherwise difficult to address in vivo. By monitoring the dynamics of gene expression during direct reprogramming of astrocytes into different neuronal subtypes via the activation of Neurog2 and Ascl1, we demonstrate that these proneural factors control largely different neurogenic programs. Among the cascades induced, however, we identified a common subset of transcription factors required for both Neurog2- and Ascl1-induced reprogramming, and combinations of these factors comprising NeuroD4 were sufficient to generate functional neurons. Notably, during astrocyte maturation REST prevents Neurog2 from binding to the NeuroD4 locus that becomes then enriched with histone H4 lysine 20 tri-methylation.
Publication Title
Transcriptional Mechanisms of Proneural Factors and REST in Regulating Neuronal Reprogramming of Astrocytes.
Sample Metadata Fields
Sex, Specimen part, Treatment, Time
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Since the discovery of radial glia as the source of neurons, their heterogeneity in regard to neurogenesis has been described by clonal and time-lapse analysis in vitro. However, the molecular determinants specifying neurogenic radial glia differently from radial glia that mostly self-renew remain ill-defined. Here, we isolated two radial glial subsets that co-exist at mid-neurogenesis in the developing cerebral cortex and their immediate progeny. While one subset generates neurons directly, the other is largely non-neurogenic but also gives rise to Tbr2-positive basal precursors, thereby contributing indirectly to neurogenesis. Isolation of
Publication Title
Prospective isolation of functionally distinct radial glial subtypes--lineage and transcriptome analysis.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 7 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Evolution of the mammalian brain encompassed a remarkable increase in size of cerebral cortex, including tangential and radial expansion, but the mechanisms underlying these key parameters are still largely unknown. Here, we identified the novel DNA associated protein TRNP1 as a regulator of cerebral cortical expansion in both these dimensions. Gain and loss of function experiments in the mouse cerebral cortex in vivo demonstrate that high Trnp1 levels promote neural stem cell self-renewal and tangential expansion, while lower levels promote radial expansion resulting in a potent increase in the generation of intermediate progenitors and outer radial glial cells resulting in folding of the otherwise smooth murine cerebral cortex. Remarkably, TRNP1 expression levels exhibit regional differences also in the cerebral cortex of human fetuses anticipating radial or tangential expansion respectively. Thus, the dynamic regulation of TRNP1 is critical to regulate tangential and radial expansion of the cerebral cortex in mammals.
Publication Title
Prospective isolation of functionally distinct radial glial subtypes--lineage and transcriptome analysis.
Sample Metadata Fields
Sex, Specimen part
View Samples