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Data set for thesis submission entitled "Characterization of cardiac defects associated with Vinculin deletion in cardiac neural crest"

posted on 2023-03-13, 01:44 authored by Yu Ming WongYu Ming Wong


Vinculin (Vcl) is an adaptor protein of adherens junctions and focal adhesions. Cardiac

neural crest cell (CNCC) is a key population of progenitor cells regulating the cardiac outflow

tract (OFT) septation and valvulogenesis. Neurocristopathy patients carrying a loss-of-function

mutation in VCL presented various cardiac defects. A mouse model of NCC-specific knockout

of Vcl (Vcl-cKO) nicely phenocopied the cardiac defects as seen in the patients and exhibited

hyperplastic semilunar valves. Here, we aimed to characterize the molecular mechanisms

underlying the NCC-mediated valvulogenesis using Vcl-cKO.

Single cell transcriptomic analysis of CNCC progenies in E13.5 embryonic hearts

revealed that transforming growth factor-b (TGF-b) signaling is severely interrupted in the

mutant cells. More intriguingly, subsequent immunohistochemistry analysis (IHC) further

discovered a novel role of TGF-b signal in mediating the crosstalk between CNCC- and

endothelial- derived valvular interstitial cells (VICs) and their activation during valvulogenesis.

Defective TGF-b signal interrupted the activation of CNCC-derived VICs, leading to retarded

myocardialization and failure in valve remodeling.

While TGF-b signaling disruption was observed at E10.5 interrupting the formation of

endocardial cushion, temporal tracking of TGF-b activation in valvular interstitial cells from

E10.5 to E15.5 further revealed two waves of TGF-b signaling activation in semilunar

valvulogenesis, contributing to separate developmental processes. The disruption of TGF-b

signaling was found with a delayed upregulation from E13.5 to E15.5 in mutant VICs. Together

with cell proliferation and apoptosis assays, it might suggest the hyperplastic SLV observed in

Vcl-cKO mutant was associated with aberrant proliferation of CNCC-VICs through delayed

TGF-b signaling activation.

In summary, it was found that Vcl plays a crucial role in mediating semilunar

valvulogenesis through TGF-b signaling regulation in CNCCs. CNCCs contributed essentially

as a TGF-b signaling hub to EndoMT and VIC activation and differentiation.


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