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2014 ; 141
(12
): 2446-51
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Notch signaling functions in lymphatic valve formation
#MMPMID24917500
Murtomaki A
; Uh MK
; Kitajewski C
; Zhao J
; Nagasaki T
; Shawber CJ
; Kitajewski J
Development
2014[Jun]; 141
(12
): 2446-51
PMID24917500
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Collecting lymphatic ducts contain intraluminal valves that prevent backflow. In
mice, lymphatic valve morphogenesis begins at embryonic day 15.5 (E15.5). In the
mesentery, Prox1 expression is high in valve-forming lymphatic endothelial cells,
whereas cells of the lymphatic ducts express lower levels of Prox1. Integrin ?9,
fibronectin EIIIA, Foxc2, calcineurin and the gap junction protein Cx37 are
required for lymphatic valve formation. We show that Notch1 is expressed
throughout the developing mesenteric lymphatic vessels at E16.5, and that, by
E18.5, Notch1 expression becomes highly enriched in the lymphatic valve
endothelial cells. Using a Notch reporter mouse, Notch activity was detected in
lymphatic valves at E17.5 and E18.5. The role of Notch in lymphatic valve
morphogenesis was studied using a conditional lymphatic endothelial cell driver
either to delete Notch1 or to express a dominant-negative Mastermind-like
(DNMAML) transgene. Deletion of Notch1 led to an expansion of Prox1(high) cells,
a defect in Prox1(high) cell reorientation and a decrease in integrin ?9
expression at sites of valve formation. Expression of DNMAML, which blocks all
Notch signaling, resulted in a more severe phenotype characterized by a decrease
in valves, failure of Prox1(high) cells to cluster, and rounding of the nuclei
and decreased fibronectin-EIIIA expression in the Prox1(high) cells found at
valve sites. In human dermal lymphatic endothelial cells, activation of Notch1 or
Notch4 induced integrin ?9, fibronectin EIIIA and Cx37 expression. We conclude
that Notch signaling is required for proper lymphatic valve formation and
regulates integrin ?9 and fibronectin EIIIA expression during valve
morphogenesis.
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