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2016 ; 143
(6
): 1041-54
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Wnt/?-catenin signaling enables developmental transitions during valvulogenesis
#MMPMID26893350
Bosada FM
; Devasthali V
; Jones KA
; Stankunas K
Development
2016[Mar]; 143
(6
): 1041-54
PMID26893350
show ga
Heart valve development proceeds through coordinated steps by which endocardial
cushions (ECs) form thin, elongated and stratified valves. Wnt signaling and its
canonical effector ?-catenin are proposed to contribute to
endocardial-to-mesenchymal transformation (EMT) through postnatal steps of
valvulogenesis. However, genetic redundancy and lethality have made it
challenging to define specific roles of the canonical Wnt pathway at different
stages of valve formation. We developed a transgenic mouse system that provides
spatiotemporal inhibition of Wnt/?-catenin signaling by chemically inducible
overexpression of Dkk1. Unexpectedly, this approach indicates canonical Wnt
signaling is required for EMT in the proximal outflow tract (pOFT) but not
atrioventricular canal (AVC) cushions. Furthermore, Wnt indirectly promotes pOFT
EMT through its earlier activity in neighboring myocardial cells or their
progenitors. Subsequently, Wnt/?-catenin signaling is activated in cushion
mesenchymal cells where it supports FGF-driven expansion of ECs and then AVC
valve extracellular matrix patterning. Mice lacking Axin2, a negative Wnt
regulator, have larger valves, suggesting that accumulating Axin2 in maturing
valves represents negative feedback that restrains tissue overgrowth rather than
simply reporting Wnt activity. Disruption of these Wnt/?-catenin signaling roles
that enable developmental transitions during valvulogenesis could account for
common congenital valve defects.
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