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Series GSE103999 Query DataSets for GSE103999
Status Public on Feb 01, 2018
Title CREB Coactivators CRTC2 and CRTC3 Modulate Bone Marrow Hematopoiesis
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Populations of circulating immune cells are maintained in equilibrium through signals that enhance the retention or egress of hematopoietic stem cells (HSCs) from bone marrow (BM). Prostaglandin E2 (PGE2) stimulates HSC renewal and engraftment, for example, via induction of the cAMP pathway. Triggering of PGE2 receptors increases HSC survival in part via the PKA-mediated induction of the CREB signaling pathway. PKA stimulates cellular gene expression by phosphorylating CREB at Ser133 and by promoting the dephosphorylation of the cAMP Responsive Transcriptional Coactivators (CRTCs). We show here that disruption of both CRTC2 and CRTC3 causes embryonic lethality, and that a single allele of either CRTC2 or CRTC3 is sufficient for viability. CRTC2 knockout mice that express one CRTC3 allele (CRTC2/3m mice) develop neutrophilia and splenomegaly in adulthood due to the up-regulation of Granulocyte-Colony Stimulating Factor (G-CSF); these effects are reversed following administration of neutralizing anti-G-CSF antiserum. Adoptive transfer of CRTC2/3m BM conferred the splenomegaly/neutrophilia phenotype on WT recipients. Indeed, targeted disruption of both CRTC2 and CRTC3 in stromal cells with a mesenchymal Prx1-Cre transgene also promoted this phenotype. Depletion of CRTC2/3 was found to decrease the expression of Suppressor of Cytokine Signaling 3 (SOCS3), leading to increases in STAT3 phosphorylation and to the induction of CEBPb, a key regulator of the G-CSF gene. As small molecule inhibition of JAK activity disrupted CEBPb induction and reduced G-CSF expression in CRTC2/3m stromal cells, our results demonstrate how cross-coupling between the CREB/CRTC and JAK/STAT pathways contributes to BM homeostasis.
Overall design Primary mouse SVF cells from wild-type or CRTC2/CRTC3 compound heterozygote mice were used to interrogate the impact of FSK exposure and CREB activity on cAMP dependent gene regulation in primary SVF cells
Contributor(s) Kim J, Hedrick S, Tsai W, Wiater E, Lay JL, Kaestner KH, Leblanc M, Loar A, Montminy M, Wiater E
Citation(s) 29078378
Submission date Sep 19, 2017
Last update date Jun 19, 2019
Contact name Ezra Wiater
Phone (858)453-4100
Organization name Salk Institute For Biological Studies
Department PBL
Lab Montminy
Street address 10010 N Torrey Pines Rd
City San Diego
State/province CA
ZIP/Postal code 92037
Country USA
Platforms (1)
GPL16417 Illumina MiSeq (Mus musculus)
Samples (4)
GSM2787561 WT-mStromal-SVF-NT
GSM2787562 WT-mStromal-SVF-FSK
GSM2787563 Het-mStromal-SVF-NT
BioProject PRJNA407926
SRA SRP118088

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Supplementary file Size Download File type/resource
GSE103999_mStromal_WTvHet_gene_exp.diff.gz 4.1 Mb (ftp)(http) DIFF
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Processed data are available on Series record

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