YAP/TAZ-CDC42 signaling regulates vascular tip cell migration

Area of Science:

• Cell Biology
• Developmental Biology
• Molecular Biology

Background:

• Angiogenesis and vascular remodeling are crucial for organ development.
• The Hippo signaling pathway regulates organ size and cell proliferation.
• Yeast and drosophila homologue of the Hippo pathway (YAP) and Tafazzin (TAZ) are key downstream effectors.

Purpose of the Study:

• To investigate the role of YAP and TAZ in vascular endothelial cell (EC) proliferation and migration during retinal angiogenesis.
• To elucidate the regulatory mechanisms of YAP/TAZ in ECs and their impact on angiogenesis.
• To explore the connection between Hippo signaling, EC migration, and the small GTPase CDC42.

Main Methods:

• Gene dosage-dependent analysis of YAP and TAZ in retinal angiogenesis.
• Investigating the effects of Lats1/2 deletion on YAP/TAZ localization and EC migration.
• Utilizing a constitutively active cytoplasmic YAP mutant (YAPS127D) to assess rescue effects.
• Examining the regulatory role of cytoplasmic YAP in CDC42 activity.
• Assessing the impact of CDC42 deletion on endothelial cell migration.

Main Results:

• YAP and TAZ are essential for EC proliferation and migration in a gene dosage-dependent manner during retinal angiogenesis.
• Nuclear translocation of YAP/TAZ, induced by Lats1/2 deletion, inhibits EC migration, mimicking Yap/Taz deficiency.
• Overexpression of cytoplasmic YAP (YAPS127D) partially rescues migration defects in Yap/Taz-deficient cells.
• Cytoplasmic YAP positively regulates CDC42 activity.
• CDC42 deletion leads to significant defects in endothelial cell migration.

Conclusions:

• Cytoplasmic YAP/TAZ play a critical role in promoting EC migration by activating CDC42.
• This study reveals a novel function of cytoplasmic YAP/TAZ in regulating angiogenesis through the CDC42 pathway.
• Findings provide new insights into Hippo signaling in endothelial cells and its regulation of vascular network formation.