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| 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
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| 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.
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| 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
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| 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 |
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| Submission date |
Sep 19, 2017 |
| Last update date |
Jun 19, 2019 |
| Contact name |
Ezra Wiater |
| E-mail(s) |
wiater@salk.edu
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| Phone |
(858)453-4100
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| Organization name |
Salk Institute For Biological Studies
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| Department |
PBL
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| Lab |
Montminy
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| Street address |
10010 N Torrey Pines Rd
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| City |
San Diego |
| State/province |
CA |
| ZIP/Postal code |
92037 |
| Country |
USA |
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| Platforms (1) |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA407926 |
| SRA |
SRP118088 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE103999_mStromal_WTvHet_gene_exp.diff.gz |
4.1 Mb |
(ftp)(http) |
DIFF |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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