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Cdc42 is a Ras-related GTPase that plays an important role in regulation of actin cytoskeletal architecture. Blocking the ability of Cdc42 to activate its effectors has been shown to inhibit a range of cellular functions including cell polarization, migration, proliferation and differentiation. Consistent with its critical roles in vitro, the inactivation of Cdc42 in mice resulted in embryonic lethality before E6.5. The early embryonic lethal phenotype of Cdc42-null mice has made it not useful for studies on the interesting questions of the roles and mechanisms of Cdc42 in the vascular development. To overcome this problem, we have generated an endothelial cell (EC) specific Cdc42 knockout mouse line by crossing Cdc42/flox mice with vascular endothelial cadherin Cre mice. Our results have demonstrated that the deletion of Cdc42 in ECs resulted in embryonic lethality with severe edema. Whole mount immunofluorescence staining showed mesentery collecting lymphatic vessel maturation and valve formation defects. Interestingly, lymphangiogenesis in the intestine wall was totally disrupted in Cdc42 EC knockout embryos. Moreover, we analyzed the role of Cdc42 in lymphatic vessel formation in the skin. We found that Cdc42 is required for tip cells filopodia formation and the deletion of Cdc42 in endothelial cells impaired lymphatic vessel sprouting, branching and the mutant lymphatic vessels displayed blunt-ended, bulbous lymphatic. We also noted that the size of lymphatic lumen was significantly increased. Taken together, our data suggested that Cdc42 plays an essential role in lymphatic branching, maturation and valve formation during development.

Footnotes

Author Disclosures: Y. Jin: None. Y. Liu: None. H. Chen: None. R. Wang: None. H. Si: None. S. Srinivasan: None. S. Zhang: None. M. Muthuchamy: None. D. Zawieja: None. X. Peng: None.

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