Search

Megakaryocytes (MKs), the precursors of blood platelets, are large, polyploid cells residing mainly in the bone marrow. We have previously shown that balanced signaling of the Rho GTPases RhoA and Cdc42 is critical for correct MK localization at bone marrow sinusoids in vivo. Using conditional RhoA/Cdc42 double-knockout (DKO) mice, we reveal here that RhoA/Cdc42 signaling is dispensable for the process of polyploidization in MKs but essential for cytoplasmic MK maturation. Proplatelet formation is virtually abrogated in the absence of RhoA/Cdc42 and leads to severe macrothrombocytopenia in DKO animals. The MK maturation defect is associated with downregulation of myosin light chain 2 (MLC2) and β1-tubulin, as well as an upregulation of LIM kinase 1 and cofilin-1 at both the mRNA and protein level and can be linked to impaired MKL1/SRF signaling. Our findings demonstrate that MK endomitosis and cytoplasmic maturation are separately regulated processes, and the latter is critically controlled by RhoA/Cdc42. [Display omitted] • RhoA/Cdc42 DKO mice display severe macrothrombocytopenia and defective hemostasis • DKO megakaryocytes show defective cytoplasmic maturation but normal endomitosis • Loss of RhoA/Cdc42 signaling abolishes proplatelet formation • RhoA/Cdc42 signaling regulates gene expression during megakaryocyte maturation Using conditional knockout mice, Heib et al. reveal that signaling of the Rho GTPases RhoA/Cdc42 regulates gene expression programs essential for cytoplasmic megakaryocyte maturation and platelet production, whereas megakaryocyte endomitosis is not affected. As a result, DKO mice display a dramatic macrothrombocytopenia and defective hemostasis. [ABSTRACT FROM AUTHOR]