Tyro3受体酪氨酸激酶亚家庭在调节小鼠红细胞发生中的功能
摘要
Tyro3受体酪氨酸激酶(receptor tyrosine kinases，RTKs)亚家族包括Tyro3，Axl和Mer三个成员，配体是Gas6和Protein S。它们广泛表达于哺乳动物的神经、免疫、生殖、造血和血管等组织中，并在神经发育、免疫调节、精子发生、NK细胞分化、血小板功能以及血管发生中发挥着重要的作用。Tyro3 RTKs亚家族这三个受体虽然在造血系统中均有表达，但在造血中的功能所知甚少。本文主要研究Tyro3 RTKs对红细胞发生的调节作用。
1．用RT-PCR，Western blot以及免疫细胞化学的方法，检测Tyro3 RTKs亚家族三个成员在红系细胞和骨髓基质细胞中的表达。结果发现红细胞发生的各个阶段都表达Axl和Mer，但不表达Tyro3。骨髓基质细胞不仅表达这三个受体，而且还表达其配体Gas6和Protein S。提示这三个受体及其配体可能影响红系造血。
2．对基因敲除小鼠的表型分析发现，Axl~(-/-)Mer~(-/-)(AM)小鼠骨髓内红系细胞，特别是成熟红细胞的数量显著下降。但单基因敲除(Axl~(-/-)和Mer~(-/-)，简称A和M)小鼠骨髓中红系细胞的数量未见异常。表明Axl和Mer在红细胞发生中起着重要的调节作用。
3．AM小鼠肝、脾体积增大，重量增加。肝脏中出现造血岛；脾脏中红髓增生明显。流式细胞分析发现脾脏中存在大量的红系造血细胞。说明AM小鼠骨髓造血功能受损，导致髓外造血发生。
4．集落形成实验发现，AM小鼠骨髓内的红系祖细胞明显增多。流式细胞仪分析表明，AM小鼠骨髓内早期的红系细胞的比例是正常小鼠的2倍，但是祖细胞以后的发育阶段—早、中、晚幼红细胞以及成熟红细胞明显减少。流式分析AM小鼠骨髓内的红系祖细胞的细胞周期和凋亡均没有变化。说明AM小鼠骨髓内红细胞发生发育阻滞在造血祖细胞阶段，且Axl和Mer对红系祖细胞具有调控作用。
5．正常小鼠骨髓移植到致死剂量γ照射的AM小鼠体内，骨髓造血功能正常。相反AM小鼠骨髓细胞移植到致死剂量γ照射的正常小鼠体内，骨髓造血功能异常，与AM小鼠骨髓造血一致。混合移植实验，将正常和AM小鼠骨髓细胞等量混合移植到致死剂量γ照射的正常小鼠体内，骨髓造血功能正常。说明AM小鼠骨髓内的红系造血异常并非由骨髓造血微环境的改变引起的，而是由红系细胞自身分化障碍引起的。
6．为进一步认识Axl和Mer调节红细胞发生的分子机理，我们研究了它们对红细胞发生相关基因的表达作用，结果发现AM小鼠中与红系发生密切相关的转录因子GATA-1和调控红细胞发育的重要细胞因子Epo受体(EpoR)表达明显降低。在体外，rhGas6可以诱导正常小鼠早期红细胞表达GATA-1和-EpoR，而对AM小鼠几乎不起作用。推测Gas6/TAM RTKs系统可能通过调控GATA-1及EpoR的表达来调节红细胞发生。单基因敲除(A和M)小鼠红细胞中GATA-1，EpoR的表达正常，表明Axl和Mer对红细胞发生的调节作用可以互相代偿。
Axl,Tyro3 and Mer are three members of a recently characterized receptor tyrosinekinase (RTK) family that share a conserved intracellular tyrosine kinase domain and anextracellular domain similar to those seen in cell adhesion molecules.These RTKs bind thevitamin K-dependent protein growth-arrest-specific gene 6 (Gas6),which is structurallyrelated to the protein S anticoagulation factor.Gas6/Tyro3 RTKs signaling regulates cellgrowth and survival.They are widely expressed in various mammalian tissues,such asnervous,immune,reproductive,vascular and hematopoietic tissues,and play an importantrole in regulating spermatogenesis,immune homeostasis,platelet functions,NK cellsdifferentiation,angiogenesis and vascular remodeling.Although they are expressed inhematopoietic system,the role of the three receptors in hematopoiesis is unknown.In thisstudy,we demonstrate that Axl and Mer are critical in regulating erythropoiesis.
1.By RT-PCR,Western blot and Immunocytochemistry,we found that Axl and Mer,butnot Tyro3,are expressed in all stages of developing erythroid cells.Marrow stromal cellsexpressed not only all three receptors,but also their common ligands,Gas6 and Protein S.
2.We found Axl~(-/-)Mer~(-/-) (AM) bone marrows to contain fewer total cells than wild-typecontrols.In contrast,the bone marrow cellularity in single mutant mice (Axl~(-/-) or Mer~(-/-))were not altered significantly compared to wild-type controls.The results suggest that Axland Mer regulate erythropoiesis.
3.Anemia was not observed in AM mice.However,we found that the spleens of AM micewere enlarged up to 4 times the wild-type controls.Histological examination showed anevident expansion of red pulps in the spleen.The flow cytometry anlysis showed thepercentage of all stages erythroblasts in AM spleen was increased.The livers of AM miceexpand up to 3.5-fold,and the evident erythropoiesis islands appeared in AM livers.Theresults suggest compensatory extramedullary erythropoiesis occurs in liver and spleen ofAM mice.
4.Although a significant reduction in erythroid cells was observed in AM bone marrows,the number of CFU-E progenitors was increased.However,there was no significantdifference in number of BFU-E progenitors between AM and wild-type bone marrows.Thenumbers of erythroid progenitors in AM bone marrow is twice more than that in wild-typecontrol.However,the numbers of the early,intermediate,late erythroiblasts and mature redcells were significantly reduced in AM bone marrows.By analysis of annexin-V positivecell,we found that apoptosis rate of the different populations of erythroid cells was notsignificantly altered in AM bone marrows and spleens compared to controls.In order toanalyze growth rate of the erythroid progenitors,they were gated and performed akaryotype analysis.The result showed a comparable cell cycle of the erythroid progenitorsin wild-type and AM bone marrows.Taken together,the results suggest that thedifferentiation of erythroid cells is blocked at the transition of the erythroid progenitors toproerythroblasts,which results in the accumulation of erythroid progenitors and thereduction of erythroblasts in AM bone marrow.
5.AM mice receiving wild-type bone marrow cells displayed a normal erythropoiesis.Conversely,wild-type mice engrafted with AM bone marrow cells exhibit an impairederythropoiesis,and have a similar distribution of erythroid cells with that in AM mice.Andwild-type mice engrafted with wild-type and AM bone marrow cells also showed a normalerythropoiesis.These results demonstrate that the defect in development of AM erythroidcells is cell autonomous.
6.With an effort to reveal the molecular mechanisms underlying the defect oferythropoiesis in AM mice,we found that the expression of GATA-1 and EpoR decline inerythroid progenitors of AM mice.Gas6 increases significantly the expression of EpoRand GATA-1 in cultured erythroid progenitors.In contrast,the Gas6 induction of EpoR andGATA-1 mRNA in vitro was completely blocked in AM erythroblasts.Notably,Gas6up-regulated the expression of EpoR and GATA-1 in the single mutant (Axl~(-/-) or Mer~(-/-))erythroblasts.The results indicate that Axl and Mer may participate in erythropoiesis in redundant manner through regulating EpoR and GATA-1 expression.
1．用RT-PCR，Western blot以及免疫细胞化学的方法，检测Tyro3 RTKs亚家族三个成员在红系细胞和骨髓基质细胞中的表达。结果发现红细胞发生的各个阶段都表达Axl和Mer，但不表达Tyro3。骨髓基质细胞不仅表达这三个受体，而且还表达其配体Gas6和Protein S。提示这三个受体及其配体可能影响红系造血。
2．对基因敲除小鼠的表型分析发现，Axl~(-/-)Mer~(-/-)(AM)小鼠骨髓内红系细胞，特别是成熟红细胞的数量显著下降。但单基因敲除(Axl~(-/-)和Mer~(-/-)，简称A和M)小鼠骨髓中红系细胞的数量未见异常。表明Axl和Mer在红细胞发生中起着重要的调节作用。
3．AM小鼠肝、脾体积增大，重量增加。肝脏中出现造血岛；脾脏中红髓增生明显。流式细胞分析发现脾脏中存在大量的红系造血细胞。说明AM小鼠骨髓造血功能受损，导致髓外造血发生。
4．集落形成实验发现，AM小鼠骨髓内的红系祖细胞明显增多。流式细胞仪分析表明，AM小鼠骨髓内早期的红系细胞的比例是正常小鼠的2倍，但是祖细胞以后的发育阶段—早、中、晚幼红细胞以及成熟红细胞明显减少。流式分析AM小鼠骨髓内的红系祖细胞的细胞周期和凋亡均没有变化。说明AM小鼠骨髓内红细胞发生发育阻滞在造血祖细胞阶段，且Axl和Mer对红系祖细胞具有调控作用。
5．正常小鼠骨髓移植到致死剂量γ照射的AM小鼠体内，骨髓造血功能正常。相反AM小鼠骨髓细胞移植到致死剂量γ照射的正常小鼠体内，骨髓造血功能异常，与AM小鼠骨髓造血一致。混合移植实验，将正常和AM小鼠骨髓细胞等量混合移植到致死剂量γ照射的正常小鼠体内，骨髓造血功能正常。说明AM小鼠骨髓内的红系造血异常并非由骨髓造血微环境的改变引起的，而是由红系细胞自身分化障碍引起的。
6．为进一步认识Axl和Mer调节红细胞发生的分子机理，我们研究了它们对红细胞发生相关基因的表达作用，结果发现AM小鼠中与红系发生密切相关的转录因子GATA-1和调控红细胞发育的重要细胞因子Epo受体(EpoR)表达明显降低。在体外，rhGas6可以诱导正常小鼠早期红细胞表达GATA-1和-EpoR，而对AM小鼠几乎不起作用。推测Gas6/TAM RTKs系统可能通过调控GATA-1及EpoR的表达来调节红细胞发生。单基因敲除(A和M)小鼠红细胞中GATA-1，EpoR的表达正常，表明Axl和Mer对红细胞发生的调节作用可以互相代偿。
Axl,Tyro3 and Mer are three members of a recently characterized receptor tyrosinekinase (RTK) family that share a conserved intracellular tyrosine kinase domain and anextracellular domain similar to those seen in cell adhesion molecules.These RTKs bind thevitamin K-dependent protein growth-arrest-specific gene 6 (Gas6),which is structurallyrelated to the protein S anticoagulation factor.Gas6/Tyro3 RTKs signaling regulates cellgrowth and survival.They are widely expressed in various mammalian tissues,such asnervous,immune,reproductive,vascular and hematopoietic tissues,and play an importantrole in regulating spermatogenesis,immune homeostasis,platelet functions,NK cellsdifferentiation,angiogenesis and vascular remodeling.Although they are expressed inhematopoietic system,the role of the three receptors in hematopoiesis is unknown.In thisstudy,we demonstrate that Axl and Mer are critical in regulating erythropoiesis.
1.By RT-PCR,Western blot and Immunocytochemistry,we found that Axl and Mer,butnot Tyro3,are expressed in all stages of developing erythroid cells.Marrow stromal cellsexpressed not only all three receptors,but also their common ligands,Gas6 and Protein S.
2.We found Axl~(-/-)Mer~(-/-) (AM) bone marrows to contain fewer total cells than wild-typecontrols.In contrast,the bone marrow cellularity in single mutant mice (Axl~(-/-) or Mer~(-/-))were not altered significantly compared to wild-type controls.The results suggest that Axland Mer regulate erythropoiesis.
3.Anemia was not observed in AM mice.However,we found that the spleens of AM micewere enlarged up to 4 times the wild-type controls.Histological examination showed anevident expansion of red pulps in the spleen.The flow cytometry anlysis showed thepercentage of all stages erythroblasts in AM spleen was increased.The livers of AM miceexpand up to 3.5-fold,and the evident erythropoiesis islands appeared in AM livers.Theresults suggest compensatory extramedullary erythropoiesis occurs in liver and spleen ofAM mice.
4.Although a significant reduction in erythroid cells was observed in AM bone marrows,the number of CFU-E progenitors was increased.However,there was no significantdifference in number of BFU-E progenitors between AM and wild-type bone marrows.Thenumbers of erythroid progenitors in AM bone marrow is twice more than that in wild-typecontrol.However,the numbers of the early,intermediate,late erythroiblasts and mature redcells were significantly reduced in AM bone marrows.By analysis of annexin-V positivecell,we found that apoptosis rate of the different populations of erythroid cells was notsignificantly altered in AM bone marrows and spleens compared to controls.In order toanalyze growth rate of the erythroid progenitors,they were gated and performed akaryotype analysis.The result showed a comparable cell cycle of the erythroid progenitorsin wild-type and AM bone marrows.Taken together,the results suggest that thedifferentiation of erythroid cells is blocked at the transition of the erythroid progenitors toproerythroblasts,which results in the accumulation of erythroid progenitors and thereduction of erythroblasts in AM bone marrow.
5.AM mice receiving wild-type bone marrow cells displayed a normal erythropoiesis.Conversely,wild-type mice engrafted with AM bone marrow cells exhibit an impairederythropoiesis,and have a similar distribution of erythroid cells with that in AM mice.Andwild-type mice engrafted with wild-type and AM bone marrow cells also showed a normalerythropoiesis.These results demonstrate that the defect in development of AM erythroidcells is cell autonomous.
6.With an effort to reveal the molecular mechanisms underlying the defect oferythropoiesis in AM mice,we found that the expression of GATA-1 and EpoR decline inerythroid progenitors of AM mice.Gas6 increases significantly the expression of EpoRand GATA-1 in cultured erythroid progenitors.In contrast,the Gas6 induction of EpoR andGATA-1 mRNA in vitro was completely blocked in AM erythroblasts.Notably,Gas6up-regulated the expression of EpoR and GATA-1 in the single mutant (Axl~(-/-) or Mer~(-/-))erythroblasts.The results indicate that Axl and Mer may participate in erythropoiesis in redundant manner through regulating EpoR and GATA-1 expression.
引文
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