A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis
A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis
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DOI：
10.1038/ncomms15838
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发表时间：
2017-06-15
影响因子：
16.6
通讯作者：
Nieswandt, Bernhard
中科院分区：
文献类型：
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作者：
Duetting, Sebastian;Gaits-Iacovoni, Frederique;Nieswandt, Bernhard
血小板由大的骨髓（BM）前体细胞巨核细胞（MK）产生，其将细胞质突起（前血小板）延伸到BM窦状隙中。控制MK向窦状隙极化和限制跨内皮穿越至前血小板的分子线索仍然未知。在这里，我们表明，小GTP酶Cdc 42和RhoA作为MK特异性机械受体GPIb下游的调节回路，以协调极化的跨内皮血小板生物合成。GPIb或Cdc 42的功能缺陷损害跨内皮前血小板形成。在没有RhoA的情况下，Cdc 42活性增加和MK超极化触发整个MK的GPIb依赖性迁移进入BM窦状隙。这些发现将Cdc 42（go-signal）和RhoA（stop-signal）定位在GPIb下游分子检查点的中心，GPIb控制跨内皮血小板生物合成。我们的研究结果可能为血小板生成障碍的治疗开辟新的途径，并有助于解释Bernard-Soulier综合征患者的血小板减少症，这是一种由GPIb-IX-V缺陷引起的出血性疾病。
Blood platelets are produced by large bone marrow (BM) precursor cells, megakaryocytes (MKs), which extend cytoplasmic protrusions (proplatelets) into BM sinusoids. The molecular cues that control MK polarization towards sinusoids and limit transendothelial crossing to proplatelets remain unknown. Here, we show that the small GTPases Cdc42 and RhoA act as a regulatory circuit downstream of the MK-specific mechanoreceptor GPIb to coordinate polarized transendothelial platelet biogenesis. Functional deficiency of either GPIb or Cdc42 impairs transendothelial proplatelet formation. In the absence of RhoA, increased Cdc42 activity and MK hyperpolarization triggers GPIb-dependent transmigration of entire MKs into BM sinusoids. These findings position Cdc42 (go-signal) and RhoA (stop-signal) at the centre of a molecular checkpoint downstream of GPIb that controls transendothelial platelet biogenesis. Our results may open new avenues for the treatment of platelet production disorders and help to explain the thrombocytopenia in patients with Bernard-Soulier syndrome, a bleeding disorder caused by defects in GPIb-IX-V.