Defective erythroid maturation in gelsolin mutant mice
Defective erythroid maturation in gelsolin mutant mice
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DOI：
10.3324/haematol.2011.052522
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发表时间：
2012-07-01
期刊：
影响因子：
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通讯作者：
Ronchi, Antonella Ellena
中科院分区：
文献类型：
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作者：
Cantu, Claudio;Bose, Francesca;Ronchi, Antonella Ellena
背景红系细胞在分化后期经历了涉及肌动蛋白细丝重塑的深刻变化。控制肌动蛋白动态的蛋白质之一是明胶蛋白，它是一种钙激活的肌动蛋白细丝切断和封端蛋白。(1)设计与方法我们通过以下方法分析了明胶蛋白在红系分化不同阶段的小鼠胎肝细胞中的表达(用逆转录聚合酶链式反应和免疫组织化学方法)，以及(Ii)研究了GSN(-/-)BALB/c小鼠胚胎和成体的红细胞生成(形态和红系培养)。GSN(-/-)胚胎显示有缺陷的红系成熟，循环有核细胞持续存在。少数成年的GSN(-/-)小鼠未能从苯肼诱导的急性贫血中恢复，显示出对应激红细胞生成的反应受损。在体外分化实验中，E13.5胎肝GSN(-/-)细胞未能发生终末成熟，这一缺陷可被细胞松弛素D部分挽救，并通过给予野生型对照样本茉莉花内酯来模拟。结论在BALB/c小鼠中，明胶蛋白缺乏改变了红细胞肌动蛋白聚合和解聚之间的平衡，导致终末成熟受损。我们认为，明胶蛋白在终末红系分化中发挥了非多余的作用，这可能是妊娠中期观察到的GSN(-/-)小鼠死亡的原因之一。
BackgroundDuring late differentiation, erythroid cells undergo profound changes involving actin filament remodeling. One of the proteins controlling actin dynamics is gelsolin, a calcium-activated actin filament severing and capping protein. Gelsolin-null (Gsn(-/-)) mice generated in a C57BL/6 background are viable and fertile.(1)Design and MethodsWe analyzed the functional roles of gelsolin in erythropoiesis by: (i) evaluating gelsolin expression in murine fetal liver cells at different stages of erythroid differentiation (using reverse transcription polymerase chain reaction analysis and immunohistochemistry), and (ii) characterizing embryonic and adult erythropoiesis in Gsn(-/-) BALB/c mice (morphology and erythroid cultures).ResultsIn the context of a BALB/c background, the Gsn(-/-) mutation causes embryonic death. Gsn(-/-) embryos show defective erythroid maturation with persistence of circulating nucleated cells. The few Gsn(-/-) mice reaching adulthood fail to recover from phenylhydrazine-induced acute anemia, revealing an impaired response to stress erythropoiesis. In in vitro differentiation assays, E13.5 fetal liver Gsn(-/-) cells failed to undergo terminal maturation, a defect partially rescued by Cytochalasin D, and mimicked by administration of Jasplakinolide to the wild-type control samples.ConclusionsIn BALB/c mice, gelsolin deficiency alters the equilibrium between erythrocyte actin polymerization and depolymerization, causing impaired terminal maturation. We suggest a non-redundant role for gelsolin in terminal erythroid differentiation, possibly contributing to the Gsn(-/-) mice lethality observed in mid-gestation.