RhoG regulates platelet granule secretion and thrombus formation in mice

Rho GTPases such as Rac, RhoA and Cdc42 are vital for normal platelet function, but the role of RhoG in platelets has not been studied. In other cells RhoG orchestrates processes integral to platelet function including actin cytoskeletal rearrangement and membrane trafficking. We therefore hypothesized that RhoG would play a critical role in platelets. Here we show that RhoG is expressed in human and in mouse platelets, and is activated by both collagen-related peptide (CRP) and thrombin stimulation. We used RhoG-/- mice to study the function of RhoG in platelets. Integrin activation and aggregation are reduced in RhoG-/- platelets stimulated by CRP, but responses to thrombin are normal. The central defect in RhoG-/- platelets is reduced secretion from alpha- and dense-granules and lysosomes following CRP stimulation. The integrin activation and aggregation defects can be rescued by ADP co-stimulation, indicating they are a consequence of diminished dense granule secretion. Defective dense granule secretion in RhoG-/- platelets limits recruitment of additional platelets to growing thrombi in flowing blood in vitro and translates into reduced thrombus formation in vivo. Interestingly, tail bleeding times are normal in RhoG-/- mice, suggesting that the functions of RhoG in platelets are particularly relevant to thrombotic disorders.