[대학원 생명과학과 세미나 안내]
연사 : 홍영권 교수 (University of Southern California)
연제 : Molecular mechanism of flow-induced lymphatic growth and function
일시 : 2020년 11월 20일 (금) 오후 5시
장소 : 온라인 화상 강의로 진행됩니다.
초청교수 : 송현규 교수
Abstract
Interstitial fluid drainage is the major function of the lymphatics. Increased fluid flow caused by functional drainage hence triggers lymphatic expansion, conceptually similar to hypoxia-triggered angiogenesis. Here, we identified a mechanotransduction pathway that translates laminar flow-induced shear stress to activation of lymphatic sprouting. While low-rate laminar flow commonly induces the classic shear stress responses in blood (BECs) and lymphatic (LECs) endothelial cells, only LECs display reduced Notch activity and increased sprouting capacity. In response to the flow, ORAI1 mediates the calcium influx in LECs and activates calmodulin to facilitate a physical interaction between KLF2, the major regulator of shear responses, and PROX1, the master regulator of lymphatic development. PROX1 and KLF2 complex binds to the promoters of DTX1 and DTX3L and upregulates their expression. Forming a heterodimeric Notch E3 ligase, DTX1 and DTX3L concertedly downregulate NOTCH1 activity and enhance lymphatic sprouting. Notably, overexpression of the calcium reporter GCaMP3 unexpectedly inhibited lymphatic sprouting presumably by disturbing calcium signaling, and endothelial-specific knockouts of Orai1 and Klf2 significantly impaired lymphatic sprouting. Moreover, loss-of-function of Dtx3L caused defective lymphatic sprouting, while gain-of-function of Dtx3L could rescue the impaired sprouting in Orai1 KO embryos. Together, we uncovered a mechanism underlying the laminar flow-induced lymphatic sprouting.