Ppp2ca条件性剔除小鼠胚胎期贫血的研究
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摘要
蛋白磷酸酶2A(PP2A)是细胞内的主要丝／苏氨酸特异性蛋白磷酸酶。它由一个催化亚基(C)和一个结构亚基(A)组成的二聚体核心酶和多种不同的调节亚基(B)所构成。PP2A的催化亚基(PP2Ac)有2种亚型,分别为PP2Acα(由Ppp2ca基因编码)和PP2Ac(3(由Ppp2cb基因编码夕。PP2Acα在大部分小鼠组织中的含量是PP2Acp的十倍,故通常被认为是最主要的PP2Ac亚型。PP2A介导的底物脱磷酸过程参与了细胞增殖、存活、分化、迁移、黏附等一系列生物过程。大量化学抑制剂、动物模型及相关研究表明PP2A磷酸酶活性对肿瘤生成,神经退变,造血发生,心脏功能维持和能量平衡等都是至关重要的。但是,PP2A活性在胚胎发育方面的功能,特别是血管和造血系统的形成,却仍然需要深入研究。
在本论文中,我们利用Tie2Cre转基因小鼠实现了Ppp2ca基因在内皮和造血祖细胞中的组织特异性剔除。大体上讲,86.7%纯合子胚胎死于或者垂死于10.5-14.5天,其余胚胎都能存活至出生。出乎意料地,纯合子胚胎不表现出任何血管生成障碍。但是,纯合子胚胎的胎肝造血功能却受到扰乱,表现为晚期祖细胞部分缺失,红系分化阻断,球蛋白表达减少。与此同时,纯合子胚胎中红系相关细胞因子的表达量,包括促红细胞生成素(FP())和干细胞因子(SCF),却没有受到影响。以上结果提示PP2Acα对红细胞的调控是以细胞自主性的方式实现的。
我们进一步分析了Ppp2ca基因剔除是否影响了最初定向造血祖细胞向胚胎肝脏的迁移。我们发现纯合子胎肝中的Linc-Kit+Sca-1+(LSK)细胞的绝对数目在胚胎期12.5天时没有改变,在胚胎期14.5天时甚至有反馈性上调。同时,我们注意到纯合子胚胎红系扩增缺陷是与细胞增殖减少和细胞凋亡增加相关联的。定向红系祖细胞程序性死亡增加是由STAT5酪氨酸磷酸化水平(pY694)降低及下游抗细胞凋亡因子Bcl-xL蛋白表达减少而引起的。与上述结果相符,用okadaic acid(OA)对原代培养的胎肝细胞进行PP2A活性抑制也能下调STAT5-Bcl-xL信号通路。
总之,本文发现Ppp2ca对胎肝造血系统发育过程具有重要作用。并且,Bcl-xL在纯合子胚胎肝脏中的表达降低可能是定向红系祖细胞存活率下降的主要原因。当然,我们正在建立Ppp2ca基因剔除,STAT5酪氨酸磷酸化水平降低,及最终胚胎期贫血的因果联系。
Protein phosphatase2A (PP2A) is the most abundant phosphatase specific for serine and threonine phosphorylation. It is composed of a common heteromeric core enzyme, that is composed of a catalytic subunit (C) and a scaffolding subunit (A), which associates with a variety of regulatory subunits (B). The catalytic subunit (PP2Ac) has two isoforms:PP2Acα (encoded by the Ppp2ca gene) and PP2Acβ(encoded by the Ppp2cb gene). PP2Acα is considered as the main functional PP2Ac isoform, because of its10-fold abundance than PP2Acβ in most mouse tissues. Dephosphorylation of substrates targeted by PP2A mediates a large variety of biological processes, such as proliferation, survival, differentiation, migration, and adhesion. The vast archive of chemical inhibitors, animal models and related studies demonstrate that PP2A phosphatase activity is important in tumorigenesis, nerve degeneration, hematopoiesis, myocardium contractile maintenance, and energy balance. However, precise knowledge about its function in developmental biology, especially the establishment of the vascular and blood system, needs to be analyzed in detail.
In this study, we deleted the floxed Ppp2co locus in endothelial and hematopoietic progenitor cells with a Tie2Cre transgene. Briefly,40%Tie2Cre+/Ppp2ca/fl/fl embryos died between E10.5and E14.5, whereas11.6%mutants were born normally. Unexpectedly, PP2Aca-deficient embryos did not manifest any defects in vascular development. However, deletion of Ppp2ca in Tie2+cells perturbed fetal liver erythropoiesis with partial loss of late progenitor cells, blockage of erythroid differentiation, and diminished globin expression. Meanwhile, the erythropoietic cytokines, including erythropoietin and stem cell factor, were not affected by loss of the Ppp2ca allele. These results indicated us that PP2Acα controls erythroid cells in a cell-autonomous manner.
We further analyzed whether the initial seeding of fetal liver with definitive hematopoietic progenitor cells was affected by Ppp2ca deletion. We found that absolute Lin-c-Kit+Sca-1+(LSK) cell numbers remained unchanged (at E12.5) or even upregulated at later stage (at E14.5) in mutant fetal livers. Meanwhile, we noticed that loss of PP2Acoα resulted in an impaired expansion of the fetal erythroid compartment that is associated with decreased proliferation and increased apoptosis. The increased programmed cell death of committed erythroid cells was accompanied by reduction in the tyrosine-phosphorylated form of STAT5(Tyr694) and total protein level of anti-apoptotic factor Bcl-xL. Consistent with these observations, inhibition of PP2A activity by okadaic acid (OA) administration on primary fetal liver cells also impaired the STAT5-Bcl-xL pathway.
Taken together, our data indicate a crucial role for Ppp2ca in fetal liver erythropoiesis during the development of the blood system. The decreased expression of Bcl-xL in mutant fetal liver cells is likely to be a principal cause of their decreased survival. However, we are still on the way to set up the links from deletion of Ppp2ca, to decreased Tyr694phosphorylation of STAT5, and finally to fetal anemia.
在本论文中,我们利用Tie2Cre转基因小鼠实现了Ppp2ca基因在内皮和造血祖细胞中的组织特异性剔除。大体上讲,86.7%纯合子胚胎死于或者垂死于10.5-14.5天,其余胚胎都能存活至出生。出乎意料地,纯合子胚胎不表现出任何血管生成障碍。但是,纯合子胚胎的胎肝造血功能却受到扰乱,表现为晚期祖细胞部分缺失,红系分化阻断,球蛋白表达减少。与此同时,纯合子胚胎中红系相关细胞因子的表达量,包括促红细胞生成素(FP())和干细胞因子(SCF),却没有受到影响。以上结果提示PP2Acα对红细胞的调控是以细胞自主性的方式实现的。
我们进一步分析了Ppp2ca基因剔除是否影响了最初定向造血祖细胞向胚胎肝脏的迁移。我们发现纯合子胎肝中的Linc-Kit+Sca-1+(LSK)细胞的绝对数目在胚胎期12.5天时没有改变,在胚胎期14.5天时甚至有反馈性上调。同时,我们注意到纯合子胚胎红系扩增缺陷是与细胞增殖减少和细胞凋亡增加相关联的。定向红系祖细胞程序性死亡增加是由STAT5酪氨酸磷酸化水平(pY694)降低及下游抗细胞凋亡因子Bcl-xL蛋白表达减少而引起的。与上述结果相符,用okadaic acid(OA)对原代培养的胎肝细胞进行PP2A活性抑制也能下调STAT5-Bcl-xL信号通路。
总之,本文发现Ppp2ca对胎肝造血系统发育过程具有重要作用。并且,Bcl-xL在纯合子胚胎肝脏中的表达降低可能是定向红系祖细胞存活率下降的主要原因。当然,我们正在建立Ppp2ca基因剔除,STAT5酪氨酸磷酸化水平降低,及最终胚胎期贫血的因果联系。
Protein phosphatase2A (PP2A) is the most abundant phosphatase specific for serine and threonine phosphorylation. It is composed of a common heteromeric core enzyme, that is composed of a catalytic subunit (C) and a scaffolding subunit (A), which associates with a variety of regulatory subunits (B). The catalytic subunit (PP2Ac) has two isoforms:PP2Acα (encoded by the Ppp2ca gene) and PP2Acβ(encoded by the Ppp2cb gene). PP2Acα is considered as the main functional PP2Ac isoform, because of its10-fold abundance than PP2Acβ in most mouse tissues. Dephosphorylation of substrates targeted by PP2A mediates a large variety of biological processes, such as proliferation, survival, differentiation, migration, and adhesion. The vast archive of chemical inhibitors, animal models and related studies demonstrate that PP2A phosphatase activity is important in tumorigenesis, nerve degeneration, hematopoiesis, myocardium contractile maintenance, and energy balance. However, precise knowledge about its function in developmental biology, especially the establishment of the vascular and blood system, needs to be analyzed in detail.
In this study, we deleted the floxed Ppp2co locus in endothelial and hematopoietic progenitor cells with a Tie2Cre transgene. Briefly,40%Tie2Cre+/Ppp2ca/fl/fl embryos died between E10.5and E14.5, whereas11.6%mutants were born normally. Unexpectedly, PP2Aca-deficient embryos did not manifest any defects in vascular development. However, deletion of Ppp2ca in Tie2+cells perturbed fetal liver erythropoiesis with partial loss of late progenitor cells, blockage of erythroid differentiation, and diminished globin expression. Meanwhile, the erythropoietic cytokines, including erythropoietin and stem cell factor, were not affected by loss of the Ppp2ca allele. These results indicated us that PP2Acα controls erythroid cells in a cell-autonomous manner.
We further analyzed whether the initial seeding of fetal liver with definitive hematopoietic progenitor cells was affected by Ppp2ca deletion. We found that absolute Lin-c-Kit+Sca-1+(LSK) cell numbers remained unchanged (at E12.5) or even upregulated at later stage (at E14.5) in mutant fetal livers. Meanwhile, we noticed that loss of PP2Acoα resulted in an impaired expansion of the fetal erythroid compartment that is associated with decreased proliferation and increased apoptosis. The increased programmed cell death of committed erythroid cells was accompanied by reduction in the tyrosine-phosphorylated form of STAT5(Tyr694) and total protein level of anti-apoptotic factor Bcl-xL. Consistent with these observations, inhibition of PP2A activity by okadaic acid (OA) administration on primary fetal liver cells also impaired the STAT5-Bcl-xL pathway.
Taken together, our data indicate a crucial role for Ppp2ca in fetal liver erythropoiesis during the development of the blood system. The decreased expression of Bcl-xL in mutant fetal liver cells is likely to be a principal cause of their decreased survival. However, we are still on the way to set up the links from deletion of Ppp2ca, to decreased Tyr694phosphorylation of STAT5, and finally to fetal anemia.
引文
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