E-MTAB-5023
Ontology highlight
ABSTRACT:
PROVIDER: E-MTAB-5023 | ExpressionAtlas | 2016-09-23
REPOSITORIES: ExpressionAtlas
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| E-MTAB-5023-analysis-methods.tsv | Tabular | |||
| E-MTAB-5023-atlasExperimentSummary.Rdata | Rdata | |||
| E-MTAB-5023-configuration.xml | Xml | |||
| E-MTAB-5023-percentile-ranks.tsv | Tabular | |||
| E-MTAB-5023.condensed-sdrf.tsv | Tabular |
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Project description:Oncogenic signaling of the niche can have a severe effect on the hematopoietic compartment and could contribute or play an active role during the development of human leukemia predisposition syndromes. To provide insights into the mechanisms that underlie this concept, as well as their relevance to disease, this study uses the leukemia predisposition syndrome Shwachman-Diamond syndrome (SDS) as a model. This leukemia predisposition syndrome is established by constitutive homozygous or compound heterozygous loss-of-function mutations in the gene SBDS. SDS is characterized by skeletal defects and a striking predisposition for the development of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Loss of Sbds in the hematopoietic compartment does not results in the induction of MDS or AML, however, could have an indirect effect on the hematopoietic system through the disruption of niche cells.<br>This submission concerns itself with gene expression profiling of transgenic mice. Osterix1 (Osx) is a zinc-finger transcriptional factor essential for osteoblast differentiation in mice and is expressed in cells of the mesenchymal lineage. A bacterial artificial chromosome (BAC) was modified such that it expressed the green fluorescent protein (GFP)::Cre recombinase (GFP::Cre) fusion protein. The artificial construct was inserted into the Osterix gene (Osx1, Sp7), enabling fusion gene GFP::Cre to be expressed from the Osx promotor (Osx1-GFP::Cre) and thereby creating transgenic mice. Cells isolated from these mice are therefore termed Osx::GFP cells. The Osx-GFP-Cre mice were crossed with Sbds f/f (flox/flox, loxp sites are inserted into the gene Sbds enabling the deletion of the region located between these loxp sites) mice to generate the transgenic Osx-GFP-Cre Sbds f/f (OCS) mice. Hence cells expressing the Osx/Sp7 gene therefore express the GFP::Cre fusion protein which enables the prospective isolation of GFP+ cells and it enables the deletion of the Sbds gene through the Cre-mediated recombination of the loxp sites.</br><br> OCS mice have skeletal defects similar to those observed in the human leukemia predisposition syndrome SDS. To obtain a detailed understanding of the underlying mechanisms Osx::GFP+ cells were prospectively isolated from bone cells suspensions, through fluorescence activated cell sorting (FACS), derived from OCS mice. Mutant OCS mice have a homozygous deletion of the Sbds gene in mesenchymal cells (e.g., osteoblasts), while wildtype mice have normal Sbds alleles. The gene expression profiles (GEPs) of both groups of mice were directly compared to determine major transcriptional changes.</br>
2016-09-22 | E-MTAB-5023 | biostudies-arrayexpress
Project description:Mucolipidosis type II (MLII) is a severe inherited multisystemic disorder caused by mutations in the GNPTAB gene. Skeletal abnormalities are a predominant feature of MLII. Here we investigate the gene expression in a knock-in mouse model for mucolipidosis type II, generated by the insertion of a cytosine in the murine Gnptab gene (c.3082insC) that is homologous to a homozygous mutation in an MLII patient. Since osteoblasts are critically involved in regulating bone development and remodeling, a genome-wide expression analysis was performed with RNA isolated from primary cultures of osteoblasts originating from MLII knock-in mice (KI) compared to RNA from wild-type (WT) osteoblasts to identify dysregulated genes involved in pathogenic mechanisms.
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Project description:Hematopoietic stem cells (HSCs) primarily reside in the bone marrow where signals generated by stromal cells regulate their self-renewal, proliferation, and trafficking. Endosteal osteoblasts and perivascular stromal cells including endothelial cells3, CXCL12-abundant reticular (CAR) cells, leptin-receptor positive stromal cells, and nestin-GFP positive mesenchymal progenitors have all been implicated in HSC maintenance. However, it is unclear if specific hematopoietic progenitor cell (HPC) subsets reside in distinct niches defined by the surrounding stromal cells and the regulatory molecules they produce. CXCL12 (stromal-derived factor-1, SDF-1) regulates both HSCs and lymphoid progenitors and is expressed by all of these stromal cell populations. Here, we selectively deleted Cxcl12 from candidate niche stromal cell populations and characterized the effect on HPCs. Deletion of Cxcl12 from mineralizing osteoblasts has no effect on HSCs or lymphoid progenitors. Deletion of Cxcl12 from osterix-expressing stromal cells, which includes CAR cells and osteoblasts, results in constitutive HPC mobilization and a loss of B lymphoid progenitors, but HSC function is normal. Cxcl12 deletion in endothelial cells results in a modest loss of long-term repopulating activity. Strikingly, deletion of Cxcl12 in nestin-negative mesenchymal progenitors using Prx1-Cre is associated with a marked loss of HSCs, long-term repopulating activity, HSC quiescence, and common lymphoid progenitors. These data suggest that osterix-expressing stromal cells comprise a distinct niche that supports B lymphoid progenitors and retains HPC in the bone marrow, while expression of CXCL12 from stromal cells in the perivascular region, including endothelial cells and mesenchymal progenitors, support HSCs. Total of three samples of two groups analyzed. Replica samples of CXCL12-abundant reticular (CAR) cells from two CXCL12-GFP knock-in mice and a combined sample of PDGFRa+ Sca+ CD45- lineage- cells from three Prx1-Cre Rosa26Ai9/+ Cxcl12gfp/+ mice were used and analyzed.
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