Dynamic Expression Profiles of β-Catenin during Murine Cardiac Valve Development

Abstract

β-catenin has been widely studied in many animal and organ systems across evolution, and gain or loss of function has been linked to a number of human diseases. Yet fundamental knowledge regarding its protein expression and localization remains poorly described. Thus, we sought to define whether there was a temporal and cell-specific regulation of β-catenin activities that correlate with distinct cardiac morphological events. Our findings indicate that activated nuclear β-catenin is primarily evident early in gestation. As development proceeds, nuclear β-catenin is down-regulated and becomes restricted to the membrane in a subset of cardiac progenitor cells. After birth, little β-catenin is detected in the heart. The co-expression of β-catenin with its main transcriptional co-factor, Lef1, revealed that Lef1 and β-catenin expression domains do not extensively overlap in the cardiac valves. These data indicate mutually exclusive roles for Lef1 and β-catenin in most cardiac cell types during development. Additionally, these data indicate diverse functions for β-catenin within the nucleus and membrane depending on cell type and gestational timing. Cardiovascular studies should take into careful consideration both nuclear and membrane β-catenin functions and their potential contributions to cardiac development and disease.

DZIP1 regulates mammalian cardiac valve development through a Cby1‐β‐catenin mechanism

“…Enhanced Wnt/β‐catenin signaling has been observed in human myxomatous valves 27‐29 . Hyperactivated β‐catenin can promote endothelial‐to‐mesenchyme transformation (EMT), endocardial proliferation, ECM remodeling and myxomatous degeneration of valves 30‐32 .…”

“…Enhanced Wnt/β‐catenin signaling has been observed in human myxomatous valves. 27 , 28 , 29 Hyperactivated β‐catenin can promote endothelial‐to‐mesenchyme transformation (EMT), endocardial proliferation, ECM remodeling and myxomatous degeneration of valves. 30 , 31 , 32 In this study as well as our previous reports on Dzip1 mutations, we observe similar findings of increased β‐catenin activities within the valves during development in a model ( Dzip1 S14R/+ ) that was previously validated as having myxomatous valves and MVP.…”

“…Our recent studies have highlighted a dynamic expression pattern between nuclear and membrane bound β‐catenin. 27 Whereas nuclear β‐catenin is present during early embryonic development, a shift to the membrane is observed during fetal gestation and is maintained after birth. This likely highlights the multifaceted role for this protein in both nuclear and membrane function.…”

Shear and hydrostatic stress regulate fetal heart valve remodeling through YAP-mediated mechanotransduction

“…(28) However, recent studies showed a discrepancy between the LEF1 and β-catenin expression in mouse embryonic heart valves, indicating that the pro-growth role of LEF1 is independent of β-catenin. (29) Here we found an extensive co-expression of LEF1 and YAP during valve remodeling. At E14.5, more than 75% of YAP expressing VIC also expressed LEF1 in both AV and OFT SL valves (Figure 2B).…”

Local fluid shear stress operates a molecular switch to drive fetal semilunar valve extension

“…The expressions of signaling programs during fetal valve remodeling are spatially and temporally regulated. 10,17,21,22 However, due to current difficulties with genetic models in studying these programs, neither the mechanisms of spatial and temporal regulations of the programs nor the environmental cues that govern them are well known. Genetic manipulation allows for the inference of the role of a gene by their global or lineagespecific absence from a tissue, which is challenging in a heterogeneously populated tissue-like valves.…”