Cdc42 is a Ras-related GTPase that plays an important role in the regulation of a range of cellular functions including cell migration, proliferation and survival. Consistent with its critical functions in vitro, the inactivation of Cdc42 in mice resulted in embryonic lethality before E6.5. To unravel the mechanisms of Cdc42 in the lymphatic development, we have generated two endothelial cell (EC)-specific Cdc42 knockout mouse lines. Our preliminary results demonstrated that the deletion of Cdc42 in ECs resulted in embryonic lethality in the perinatal stage with severe edema. Lymphatic valves are critical in guiding unidirectional lymph flow and our results demonstrated that Cdc42 is required for lymphatic valve formation. In this proposal, we will define the role of Cdc42 in VE-Cadherin-mediated intercellular cell-cell adhesions during lymphatic valve formation. We will also examine the effect of Cdc42 inactivation on VE-Cadherin-mediated adhesive force in cultured lymphatic ECs by automic force microscopy (AFM) analysis. In addition, we will determine the role and molecular mechanisms of Cdc42 on vascular endothelial growth factor receptor 3 (VEGFR3) endocytosis and its regulated signal transduction. It was reported that Cdc42 Tyr64Cys mutant resulted in lymphedema in patients. In this proposal, we will define how Cdc42 Tyr64Cys mutant affects Cdc42 functions in lymphatic ECs. These studies will generate not only significant insights into the physiological functions of Cdc42 in vivo, but also critical information for potential new therapies for pathological lymphangiogenesis in the future.
|Program type||Transformational Project Award|
|Effective start/end date||07/01/2019 → 06/30/2022|