Absence of GPIbα is responsible for aberrant membrane development during megakaryocyte maturation:: Ultrastructural study using a transgenic model
Absence of GPIbα is responsible for aberrant membrane development during megakaryocyte maturation:: Ultrastructural study using a transgenic model
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DOI：
10.1016/s0301-472x(02)00774-9
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发表时间：
2002-04-01
影响因子：
2.6
通讯作者：
Nurden, P
中科院分区：
文献类型：
--
作者：
Poujol, CR;Ware, J;Nurden, P
目标。糖蛋白Ib/IX/V复合体(GPIB-IX-V)介导暴露于内皮下层的血小板与血管性血友病因子的黏附。GPIbalpha、GPIbbeta和Gpix基因的分子缺陷导致了Bernard-Soulier综合征，在这种综合征中，血小板减少和巨大的血小板表明这种受体也参与了血小板的产生。为了研究巨型血小板是如何在体内产生的，我们使用了GPIbalpha缺陷小鼠(GPIbalpha(Null))和人类GPIbalpha转基因拯救小鼠(GPIbalpha(Null；Tg))的模型。利用电子显微镜和免疫金标记法，我们检测了这些小鼠骨髓中的巨核细胞生成情况，并开发了一种通过计算机分析来定量巨核细胞(MK)和前血小板细胞膜的方法。GPIbalpha(Null)小鼠未成熟的MK核周区膜发育异常。这导致了不发达的分界膜系统和其他超微结构的变化。结果，在成熟的MK的细胞质中很少看到组织良好的血小板区域。膜定量检测证实，GPIbalpha(空)小鼠的MK内膜池减少。尽管这些MK通常会穿过内皮屏障，但它们的迁移伴随着血管窦中异常大的MK片段或前血小板的产生，与野生型相比，内膜含量减少了约50%。在挽救的GPIbalpha(Null；Tg)模型中，GPIbalpha正常定位于MK，超微结构缺陷完全纠正。GPIba对于成熟的巨噬细胞膜的发育和分布是必不可少的。它的缺失会导致膜系统的异常分割和异常的血小板原生成。(C)2002年国际实验血液学学会。爱思唯尔科学公司出版。
Objective. The glycoprotein Ib/IX/V complex (GPIb-IX-V) mediates platelet attachment to von Willebrand factor in exposed subendothelium. Molecular defects in the genes for GPIbalpha GPIbbeta, and GPIX give rise to the Bernard-Soulier syndrome, in which thrombocytopenia and giant platelets suggest that this receptor also is involved in platelet production. To study how giant platelets are produced in vivo, we used a model of GPfbalpha-deficient mice (GPIbalpha(null)) and mice rescued with the human GPIbalpha transgene (GPIbalpha(null;Tg)).Materials and Methods. Using electron microscopy and immunogold labeling, we examined megakaryocytopoiesis in the bone marrow of these mice and developed a method to quantify the membranes of megakaryocytes (MK) and proplatelets by computer analysis.Results. Abnormal membrane development in the perinuclear zone was found in immature MK of GPIbalpha(null) mice. This led to a poorly developed demarcation membrane system and other ultrastructural changes. As a result, well-organized platelet territories were rarely seen within the cytoplasm of mature MK. Membrane quantification confirmed that MK of GPIbalpha(null) mice had a reduced internal membrane pool. Whereas these MK normally crossed the endothelial barrier, their migration was accompanied by the production of unusually large MK fragments or proplatelets in the vascular sinus with an approximately 50% decrease in internal membrane content compared to wild-type. In the rescued GPIbalpha(null;Tg) model, GPIbalpha was normally localized in MK, and there was a total correction of the ultrastructural defects.Conclusions. GPIba is essential for membrane development and distribution in maturing MK. Its absence leads to abnormal partitioning of the membrane systems and abnormal proplatelet production. (C) 2002 International Society for Experimental Hematology. Published by Elsevier Science Inc.