YAP and TAZ Negatively Regulate Prox1 During Developmental and Pathologic Lymphangiogenesis.

Area of Science:

• Vascular biology
• Cell signaling
• Developmental biology

Background:

• The Hippo pathway is crucial for organ size control, but its role in lymphatic vessel development is unclear.
• Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the main downstream effectors of the Hippo pathway.

Purpose of the Study:

• To investigate the function of YAP and TAZ in lymphatic endothelial cell (LEC) differentiation, morphogenesis, and homeostasis.
• To elucidate the molecular mechanisms by which YAP and TAZ regulate lymphatic development.

Main Methods:

• LEC-specific Yap/Taz depletion and hyperactivation in mouse models.
• Analysis of lymphatic plexus patterning, valve formation, and lymphangiogenesis.
• Investigation of Prox1, VEGF-C, NuRD, TEAD, MYC, and CDKN1C expression and function.
• Mechanistic studies involving promoter analysis and cell cycle assays.

Main Results:

• LEC-specific Yap/Taz depletion disrupted lymphatic plexus patterning and valve initiation, upregulating Prox1.
• LEC-specific YAP/TAZ hyperactivation impaired lymphatic specification and sprouting, downregulating Prox1.
• YAP/TAZ modulation affected pathological lymphangiogenesis.
• VEGF-C activated the Hippo pathway in LECs.
• YAP/TAZ hyperactivation repressed PROX1 transcription via NuRD and TEAD recruitment.
• YAP/TAZ hyperactivation dysregulated cell cycle through MYC and CDKN1C.

Conclusions:

• YAP and TAZ promote lymphatic plexus patterning and valve maintenance by negatively regulating Prox1.
• YAP and TAZ are plastic regulators of lymphatic identity.
• The Hippo signaling-mediated PROX1 transcriptional program is a novel checkpoint in LEC plasticity and pathophysiology.