Wnt11 regulates cardiac chamber development and disease during perinatal maturation
Marlin Touma, Xuedong Kang, Fuying Gao, Yan Zhao, Ashley A. Cass, Reshma Biniwale, Xinshu Xiao, Mansuoreh Eghbali, Giovanni Coppola, Brian Reemtsen, Yibin Wang
Marlin Touma, Xuedong Kang, Fuying Gao, Yan Zhao, Ashley A. Cass, Reshma Biniwale, Xinshu Xiao, Mansuoreh Eghbali, Giovanni Coppola, Brian Reemtsen, Yibin Wang
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Research Article Cardiology Genetics

Wnt11 regulates cardiac chamber development and disease during perinatal maturation

Abstract

Ventricular chamber growth and development during perinatal circulatory transition is critical for functional adaptation of the heart. However, the chamber-specific programs of neonatal heart growth are poorly understood. We used integrated systems genomic and functional biology analyses of the perinatal chamber specific transcriptome and we identified Wnt11 as a prominent regulator of chamber-specific proliferation. Importantly, downregulation of Wnt11 expression was associated with cyanotic congenital heart defect (CHD) phenotypes and correlated with O2 saturation levels in hypoxemic infants with Tetralogy of Fallot (TOF). Perinatal hypoxia treatment in mice suppressed Wnt11 expression and induced myocyte proliferation more robustly in the right ventricle, modulating Rb1 protein activity. Wnt11 inactivation was sufficient to induce myocyte proliferation in perinatal mouse hearts and reduced Rb1 protein and phosphorylation in neonatal cardiomyocytes. Finally, downregulated Wnt11 in hypoxemic TOF infantile hearts was associated with Rb1 suppression and induction of proliferation markers. This study revealed a previously uncharacterized function of Wnt11-mediated signaling as an important player in programming the chamber-specific growth of the neonatal heart. This function influences the chamber-specific development and pathogenesis in response to hypoxia and cyanotic CHDs. Defining the underlying regulatory mechanism may yield chamber-specific therapies for infants born with CHDs.

Authors

Marlin Touma, Xuedong Kang, Fuying Gao, Yan Zhao, Ashley A. Cass, Reshma Biniwale, Xinshu Xiao, Mansuoreh Eghbali, Giovanni Coppola, Brian Reemtsen, Yibin Wang

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Figure 2

Weighted gene network coexpression analysis (WGCNA) reveals stage-specific modules (gene network) in neonatal left and right ventricles.

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Weighted gene network coexpression analysis (WGCNA) reveals stage-specif...
(A and B) WGCNA dendrograms of right ventricle (RV) (A) and left ventricle (LV) (B) mRNA transcriptome. Genes with mean reads per kilobase of transcript per million mapped reads (RPKM) greater than or equal to 3 in at least one sample (3 replicates) of each category and variation greater than or equal to 0.2 across samples (FDR P value ≤ 0.05) were included from RV and LV data sets separately. Genes are clustered based on the topological overlap, a measure of connection strength. Using the R package, gene modules were constructed as groups of genes with highly similar coexpression relationships. Branches in the hierarchical clustering dendrograms correspond to modules. Color bars below the dendrograms display gene coexpression modules identified by WGCNA in RVs (A) or in LVs (B). The y axes (height) represent module significance (correlation with external trait). (C and D) Heatmaps depict expression profiles of stage-specific mRNA modules’ member genes. Thirteen stage-specific modules in RVs (C) and 8 stage-specific modules in LVs (D) are presented with upregulated genes in red, and downregulated genes in green. The expression profiles are standardized; changes are expressed in log2 scale. The numbers of genes corresponding to each module are shown in color bars. Unique stage-specific modules in LVs and RVs are defined as those with Pearson’s correlation coefficient r greater than or equal to 0.7 and P value less than or equal to 0.05 between the module eigengene (expression profile summary) and the maturation stage (P0, P3, or P7). Eigengene of a given module is presented (bar graphs). Top gene ontology (GO) term enriched in each module along with corresponding adjusted P value is listed to the right of each module. The color code is preserved. (E) Preservation plots of RV modules in LVs, and LV modules in RVs. Module size (x axis) and preservation Z-summary scores (y axis) are shown. Z summary less than 2 indicates modules were weakly or not preserved, Z summary between 2 and 10 indicates modules were moderately preserved, and Z summary greater than 10 indicates modules were well or strongly preserved. Color codes of the modules are preserved.