A lineage-restricted and divergent β-tubulin isoform is essential for the biogenesis, structure and function of blood platelets
A lineage-restricted and divergent β-tubulin isoform is essential for the biogenesis, structure and function of blood platelets
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DOI：
10.1016/s0960-9822(01)00153-1
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发表时间：
2001-04-17
期刊：
影响因子：
9.2
通讯作者：
Shivdasani, RA
中科院分区：
文献类型：
--
作者：
Schwer, HD;Lecine, P;Shivdasani, RA
背景资料：哺乳动物巨核细胞释放血小板通过一个显着的过程，细胞质碎片和从头组装的边缘微管带。该过程的细胞特异性组分包括趋异β-微管蛋白同种型β 1，其仅在血小板和巨核细胞中表达，并且是主要的同种型。这种限制性表达的功能意义，以及后生动物微管蛋白基因令人惊讶的大库，尚不清楚。真菌微管蛋白亚型在功能上似乎是多余的，所有哺乳动物β-微管蛋白都可以在各种微管中组装，而选择的苍蝇和蠕虫β-微管蛋白在精子发生和神经发生中是必不可少的。为了解决β 1-微管蛋白在其自然环境中的重要作用，我们产生了靶向基因破坏的小鼠。β 1-微管蛋白（-/-）小鼠具有血小板减少症，这是由于产生血小板前体（血小板的直接前体）的缺陷所致。循环血小板缺乏典型的盘状形状，边缘带有缺陷，微管顶减少。β 1-微管蛋白（-/-）小鼠也具有延长的出血时间，并且它们的血小板显示出对凝血酶的减弱的应答。两种可选择的微管蛋白亚型β 2和β 5过表达，β 1-微管蛋白（-/-）巨核细胞的总β-微管蛋白含量正常。然而，这些异构体组装成血小板微管的效率低得多，因此无法完全补偿β 1-微管蛋白，结论的情况下，这是第一个遗传研究，以解决哺乳动物微管蛋白异构体在体内的基本功能。这些结果确立了β 1-微管蛋白在血小板合成、结构和功能中的特殊作用。
Background: Mammalian megakaryocytes release blood platelets through a remarkable process of cytoplasmic fragmentation and de novo assembly of a marginal microtubule band. Cell-specific components of this process include the divergent beta -tubulin isoform beta1 that is expressed exclusively, and is the predominant isoform, in platelets and megakaryocytes. The functional significance of this restricted expression, and indeed of the surprisingly large repertoire of metazoan tubulin genes, is unclear. Fungal tubulin isoforms appear to be functionally redundant, and all mammalian beta -tubulins can assemble in a variety of microtubules, whereas selected fly and worm beta -tubulins are essential in spermatogenesis and neurogenesis, To address the essential role of beta1-tubulin in its natural context, we generated mice with targeted gene disruption.Results: beta1-tubulin(-/-) mice have thrombocytopenia resulting from a defect in generating proplatelets, the immediate precursors of blood platelets. Circulating platelets lack the characteristic discoid shape and have defective marginal bands with reduced microtubule ceilings. beta1-tubulin(-/-) mice also have a prolonged bleeding time, and their platelets show an attenuated response to thrombin. Two alternative tubulin isoforms, beta2 and beta5, are overexpressed, and the total beta -tubulin content of beta1-tubulin(-/-) megakaryocytes is normal. However, these isoforms assemble much less efficiently into platelet microtubules and are thus unable to compensate completely for the absence of beta1-tubulin,Conclusions: This is the first genetic study to address the essential functions of a mammalian tubulin isoform in vivo. The results establish a specialized role for beta1-tubulin in platelet synthesis, structure, and function.