Wnt11 regulates cardiac chamber development and disease during perinatal maturation
Marlin Touma, … , Brian Reemtsen, Yibin Wang
Marlin Touma, … , Brian Reemtsen, Yibin Wang
Published September 7, 2017
Citation Information: JCI Insight. 2017;2(17):e94904. https://doi.org/10.1172/jci.insight.94904.
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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 1

Transcriptome landscape in neonatal mouse heart chambers.

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Transcriptome landscape in neonatal mouse heart chambers. (A) Schematic ...
(A) Schematic representation of transcriptome analysis workflow. mRNA expression data were derived from deep RNA sequencing data sets of male C57B/6 mouse left ventricles (LVs) and right ventricles (RVs) at postnatal day 0 (P0; before the ductal closure), day 3 (P3; transition), and day 7 (P7; terminal differentiation of the vast majority of CMCs). n = 3 replicates per chamber per time point, except RVP7 (n = 2 replicates). Weighted gene network coexpression analysis (WGCNA) was performed to construct gene coexpression modules in RVs and LVs separately, followed by module preservation analysis and gene ontology analysis to identify chamber-specific genes/gene networks. (B) Principal component analysis (PCA) result of the top 1,000 varied genes (left) and the percentage of variation that corresponds to each component (right). PCA was conducted using R function prcomp. Top 1,000 varied mRNAs based on Tophat alignment results were used to generate PCAs. (C) Unsupervised hierarchical clustering of top 1,000 varied genes derived from 17 RNA-Seq data sets (n = 3 replicates per chamber per time point, except RVP7 [n = 2 replicates]). Experimental conditions of the samples are demarcated by color bars at the top according to chamber: RV (blue) and LV (pink), and time point: P0 (purple), P3 (orange), and P7 (turquoise). Samples from P3 and P7 clustered closely together away from P0, suggesting sharp transcriptome changes during the P0–P3 window. Transcripts from LVs and RVs formed distinct clusters after birth (at P3 and P7), suggesting a temporal chamber-specific transcriptome signature in postnatal heart.