Cdc42/RhoA 调控回路下游的糖蛋白 Ib 指导跨内皮血小板发生。

A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis.

机构信息

Institute of Experimental Biomedicine, University Hospital and University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany.

Rudolf Virchow Center, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany.

出版信息

Nat Commun. 2017 Jun 15;8:15838. doi: 10.1038/ncomms15838.

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.

血小板由大型骨髓（BM）前体细胞巨核细胞（MKs）产生，后者将细胞质突起（血小板前体）延伸到 BM 窦状隙中。控制 MK 向窦状隙极化并限制跨内皮 crossing 到血小板前体的分子线索尚不清楚。在这里，我们表明小 GTPases Cdc42 和 RhoA 作为 MK 特异性机械感受器 GPIb 的下游调节回路，协调极化的跨内皮血小板发生。GPIb 或 Cdc42 的功能缺失会损害跨内皮血小板前体的形成。在没有 RhoA 的情况下，增加的 Cdc42 活性和 MK 超极化会触发整个 MK 依赖 GPIb 的迁移进入 BM 窦状隙。这些发现将 Cdc42（前进信号）和 RhoA（停止信号）置于 GPIb 下游的分子检查点的中心，该检查点控制跨内皮血小板发生。我们的研究结果可能为血小板生成障碍的治疗开辟新途径，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。