CREB coactivators CRTC2 and CRTC3 modulate bone marrow hematopoiesis
CREB coactivators CRTC2 and CRTC3 modulate bone marrow hematopoiesis
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DOI：
10.1073/pnas.1712616114
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发表时间：
2017-10-01
影响因子：
11.1
通讯作者：
Montminy, Marc
中科院分区：
文献类型：
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作者：
Kim, Jeong-Ho;Hedrick, Susan;Montminy, Marc
循环免疫细胞群通过增强骨髓中造血干细胞（hsc）的保留或输出的信号维持平衡。前列腺素E2 （PGE2）通过诱导cAMP通路等方式刺激HSC的更新和植入。PGE2受体的触发部分通过pka介导的cAMP反应元件结合蛋白（CREB）信号通路的诱导增加HSC的存活。PKA通过磷酸化SerIBB上的CREB和促进camp应答转录共激活因子（crtc）的去磷酸化来刺激细胞基因表达。我们在这里表明，CRTC2和CRTC3的破坏都会导致胚胎死亡，并且CRTC2或CRTC3的单个等位基因足以维持生存。表达一个CRTC3等位基因的CRTC2敲除小鼠（CRTC2/3m小鼠）在成年期由于粒细胞集落刺激因子（G-CSF）的上调而发生中性粒细胞增多和脾肿大；这些作用在给予中和性抗g - csf抗血清后被逆转。在WT受体中，过继性转移CRTC2/3m BM可导致脾肿大/嗜中性粒细胞表型。使用间充质Prx1-Cre转基因靶向破坏基质细胞中的CRTC2和CRTC3也促进了这种表型。研究发现，缺失CRTC2/3可降低细胞因子信号传导抑制因子3 （SOCS3）的表达，导致STAT3磷酸化增加，并诱导G-CSF基因的关键调节因子CEBP β。由于JAK活性的小分子抑制破坏了CRTC2/3m基质细胞中CEBP β的诱导并降低了G-CSF的表达，我们的研究结果证明了CREB/CRTC和JAK/STAT通路之间的交叉偶联是如何促进BM稳态的。
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 through, for example, induction of the cAMP pathway. Triggering of PGE2 receptors increases HSC survival in part via the PKA-mediated induction of the cAMP response element-binding protein (CREB) signaling pathway. PKA stimulates cellular gene expression by phosphorylating CREB at SerIBB 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 in WT recipients. 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 CEBP beta, a key regulator of the G-CSF gene. As small molecule inhibition of JAK activity disrupted CEBP beta 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.