Role of hippo pathway in developmental and pathologic lymphangiogenesis = 림프관 발달과 병적 림프관 생성에서 Hippo 신호전달체계의 역할

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The Hippo pathway governs cellular differentiation, morphogenesis, and homeostasis but how it regulates these processes in lymphatic vessels is unknown. Therefore, I aimed to reveal the role of the final effectors of the Hippo pathway, YAP and TAZ (YAP/TAZ), in lymphatic endothelial cell (LEC) differentiation, morphogenesis, and homeostasis in vivo and in vitro. During mouse embryonic development, LEC-specific depletion of Yap/Taz disturbed both plexus patterning and valve initiation with upregulated Prox1. Conversely, LEC-specific YAP/TAZ hyperactivation impaired lymphatic specification and restricted lymphatic sprouting with profoundly downregulated Prox1. Notably, lymphatic YAP/TAZ depletion or hyperactivation aggravated or attenuated pathologic lymphangiogenesis in mouse cornea. Mechanistically, VEGF-C activated canonical Hippo signaling pathway in LECs. Indeed, repression of PROX1 transcription by YAP/TAZ hyperactivation was mediated by recruitment of nucleosome remodeling and histone deacetylase (NuRD) complex and endogenous binding activity of TEAD to the PROX1 promoter. Furthermore, YAP/TAZ hyperactivation enhanced MYC signaling and inhibited CDKN1C, leading to cell cycle dysregulation and aberrant proliferation. I find that YAP/TAZ play promoting roles in remodelling lymphatic plexus patterning and postnatal lymphatic valve maintenance by negatively regulating Prox1 expression. I further show that YAP/TAZ act as plastic regulators of lymphatic identity and define the Hippo signaling-mediated PROX1 transcriptional programming as a novel dynamic checkpoint underlying lymphatic endothelial cell plasticity and pathophysiology.
Advisors
Koh, Gou Youngresearcher고규영researcher
Description
한국과학기술원 :의과학대학원,
Publisher
한국과학기술원
Issue Date
2019
Identifier
325007
Language
eng
Description

학위논문(박사) - 한국과학기술원 : 의과학대학원, 2019.2,[vi, 100 p. :]

Keywords

Lymphangiogenesis▼aHippo signaling▼alymphatic endothelial cell▼aprox1 transcription factor▼aYAP/TAZ; 림프관생성▼a히포신호전달체계▼aProx1 전사 인자▼a림프관발생▼a병적림프관신생

URI
http://hdl.handle.net/10203/265076
Link
http://library.kaist.ac.kr/search/detail/view.do?bibCtrlNo=842193&flag=dissertation
Appears in Collection
MSE-Theses_Ph.D.(박사논문)
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