CREB coactivators CRTC2 and CRTC3 modulate bone marrow hematopoiesis

Area of Science:

• Hematology
• Molecular Biology
• Immunology

Background:

• Bone marrow (BM) homeostasis relies on regulating hematopoietic stem cell (HSC) retention and egress.
• Prostaglandin E2 (PGE2) signaling, via cAMP and PKA, promotes HSC renewal and survival.
• CREB (cAMP response element-binding protein) and CRTCs (cAMP-regulated transcriptional coactivators) are key mediators in these pathways.

Purpose of the Study:

• To investigate the role of CRTC2 and CRTC3 in bone marrow homeostasis and immune cell regulation.
• To elucidate the molecular mechanisms linking CRTCs to G-CSF production and HSC behavior.

Main Methods:

• Generation and analysis of CRTC2/CRTC3 mutant mice (CRTC2/3m).
• Adoptive transfer experiments using CRTC2/3m bone marrow.
• In vivo and in vitro studies involving G-CSF neutralization and JAK inhibition.
• Analysis of gene expression, including SOCS3, STAT3 phosphorylation, and CEBPβ.

Main Results:

• Disruption of CRTC2 and CRTC3 leads to embryonic lethality, with single alleles sufficient for viability.
• CRTC2/3m mice exhibit neutrophilia and splenomegaly due to elevated G-CSF.
• CRTC2/3 depletion in stromal cells decreases SOCS3, increases STAT3 phosphorylation, and induces CEBPβ, a G-CSF regulator.
• JAK inhibition reverses CEBPβ induction and G-CSF expression in CRTC2/3m stromal cells.

Conclusions:

• CRTC2 and CRTC3 are essential for maintaining bone marrow homeostasis.
• A novel cross-talk between CREB/CRTC and JAK/STAT pathways regulates G-CSF production and immune cell populations.
• Understanding this pathway is crucial for developing strategies to manage hematopoietic disorders.