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GSE27630
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- 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
- 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
- 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- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Purpose: In acute myeloid leukemia (AML) without retinoic acid receptor (RAR) rearrangement the effect of all-trans retinoic acid (ATRA) is still poorly understood despite an association of NPM1 mutation and ATRA response. Recently, PRAME (preferentially expressed antigen in melanoma) has been shown to be a dominant repressor of RAR-signaling. Experimental design: Thus, we further investigated ATRA response mechanisms, especially the impact of PRAME expression on ATRA-responsiveness by profiling gene expression in K562 cell lines. Results: Our data revealed a PRAME-expression associated gene pattern to be significantly enriched for genes involved in the retinoic acid metabolic process. In leukemia cell line models we could demonstrate that retinoic acid-regulated cell proliferation and differentiation are impacted by PRAME expression. Conclusions: PRAME seems to impair differentiation and to increase proliferation likely via blocking RAR-signaling, which might be reversed by ATRA.
Publication Title
PRAME-induced inhibition of retinoic acid receptor signaling-mediated differentiation--a possible target for ATRA response in AML without t(15;17).
Sample Metadata Fields
Treatment
View Samples- Mus musculus
- 14 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Since the discovery of adult neural stem cells, their exact identity is still under discussion. Moreover, the lack of a reproducible procedure to purify neural stem cells prospectively rather than by growing them in vitro has so far precluded their study at the transcriptome level. Here we demonstrate a novel procedure to prospectively isolate neural stem cells from the adult mouse subependymal zone on the basis of their GFAP- and prominin1-expression by fluorescence-activated cell sorting. All self-renewing, multipotent stem cells are contained in this fraction at 70% purity. The stem cell identity of these double-positive cells is further demonstrated in vivo, by using a novel split-Cre-technology for fate mapping.
Publication Title
In vivo fate mapping and expression analysis reveals molecular hallmarks of prospectively isolated adult neural stem cells.
Sample Metadata Fields
Specimen part
View Samples