Cdc42, a Ras-related GTPase that regulates the actin cytoskeleton, was recently shown to play an indispensable role in vasculogenesis and endothelial cell (EC) survival. Here, we determined whether Cdc42 also contributes to lymphatic development by generated two different Cdc42 knockout mice lines by crossing Cdc42/flox mice with either vascular endothelial cadherin-Cre (Cdh5α-Cre) mice or Prox1-CreERT2 mice. Our results demonstrated that depleting ECs of Cdc42 expression resulted in embryonic lethality with severe edema. Whole-mount immunofluorescence staining of both knockout embryos showed that the deletion of Cdc42 in ECs impaired lymphatic vessel branching and that the lymphatic lumen size significantly increased. Moreover, we found that the inactivation of Cdc42 compromised mesenteric collecting lymphatic vessel maturation and prevented valve formation. We go on to show that Cdc42 can be activated by vascular endothelial growth factor c (VEGFc) in cultured human dermal lymphatic ECs (HDLECs), and that knocking down Cdc42 expression in these cells using siRNA decreased VEGFc-induced focal adhesion kinase (FAK) phosphorylation. These findings, when taken together with the fact that inactivating FAK plus one allele of Cdc42 in ECs was sufficient to recapitulate the phenotypes of the Cdc42 EC knockout embryos, suggests that Cdc42 and FAK interact genetically during lymphatic development. In addition, Cdc42 and FAK regulated signal transduction is essential for blood and lymphatic vessel separation. Taken together, our data highlights the important role played by Cdc42 in the development of the lymphatic system.

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