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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.

SUBMITTER: Touma M

PROVIDER: S-EPMC5621892 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Wnt11 regulates cardiac chamber development and disease during perinatal maturation.

Touma Marlin M Kang Xuedong X Gao Fuying F Zhao Yan Y Cass Ashley A AA Biniwale Reshma R Xiao Xinshu X Eghbali Mansuoreh M Coppola Giovanni G Reemtsen Brian B Wang Yibin Y

JCI insight 20170907 17

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 co ...[more]

PMID: 28878122

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Project description:Chamber-specific and temporally regulated perinatal cardiac growth and maturation is critical for functional adaptation of the heart and may be altered significantly in response to perinatal stress, such as systemic hypoxia (hypoxemia), leading to significant pathology, even mortality. Understanding transcriptome regulation of neonatal heart chambers in response to hypoxemia is necessary to develop chamber-specific therapies for infants with cyanotic congenital heart defects (CHDs). We sought to determine chamber-specific transcriptome programming during hypoxemic perinatal circulatory transition. We performed transcriptome-wide analysis on right ventricle (RV) and left ventricle (LV) of postnatal day 3 (P3) mouse hearts exposed to perinatal hypoxemia. Hypoxemia decreased baseline differences between RV and LV leading to significant attenuation of ventricular patterning (AVP), which involved several molecular pathways, including Wnt signaling suppression and cell cycle induction. Notably, robust changes in RV transcriptome in hypoxemic condition contributed significantly to the AVP. Remarkably, suppression of epithelial mesenchymal transition (EMT) and dysregulation of the TP53 signaling were prominent hallmarks of the AVP genes in neonatal mouse heart. Furthermore, members of the TP53-related gene family were dysregulated in the hypoxemic RVs of neonatal mouse and cyanotic Tetralogy of Fallot hearts. Integrated analysis of chamber-specific transcriptome revealed hypoxemia-specific changes that were more robust in RVs compared with LVs, leading to previously uncharacterized AVP induced by perinatal hypoxemia. Remarkably, reprogramming of EMT process and dysregulation of the TP53 network contributed to transcriptome remodeling of neonatal heart during hypoxemic circulatory transition. These insights may enhance our understanding of hypoxemia-induced pathogenesis in newborn infants with cyanotic CHD phenotypes. KEY MESSAGES: During perinatal circulatory transition, transcriptome programming is a major driving force of cardiac chamber-specific maturation and adaptation to hemodynamic load and external environment. During hypoxemic perinatal transition, transcriptome reprogramming may affect chamber-specific growth and development, particularly in newborns with congenital heart defects (CHDs). Chamber-specific transcriptome changes during hypoxemic perinatal transition are yet to be fully elucidated. Systems-based analysis of hypoxemic neonatal hearts at postnatal day 3 reveals chamber-specific transcriptome signatures during hypoxemic perinatal transition, which involve attenuation of ventricular patterning (AVP) and repression of epithelial mesenchymal transition (EMT). Key regulatory circuits involved in hypoxemia response were identified including suppression of Wnt signaling, induction of cellular proliferation and dysregulation of TP53 network.

Project description:BackgroundCardiac fibroblasts are the main non-myocyte population responsible for extracellular matrix (ECM) production. During perinatal development, fibroblast expansion coincides with the transition from hyperplastic to hypertrophic myocardial growth. Therefore, we investigated the consequences of fibroblast loss at the time of cardiomyocyte maturation by depleting fibroblasts in the perinatal mouse.Methods and resultsWe evaluated the microenvironment of the perinatal heart in the absence of fibroblasts and the potential functional impact of fibroblast loss in regulation of cardiomyocyte cell cycle arrest and binucleation. Cre-mediated expression of diphtheria toxin A in PDGFRα expressing cells immediately after birth eliminated 70-80% of the cardiac fibroblasts. At postnatal day 5, hearts lacking fibroblasts appeared similar to controls with normal morphology and comparable numbers of endothelial and smooth muscle cells, despite a pronounced reduction in fibrillar collagen. Immunoblotting and proteomic analysis of control and fibroblast-deficient hearts identified differential abundance of several ECM proteins. In addition, fibroblast loss decreased tissue stiffness and resulted in increased cardiomyocyte mitotic index, DNA synthesis, and cytokinesis. Moreover, decellularized matrix from fibroblast-deficient hearts promoted cardiomyocyte DNA replication. While cardiac architecture was not overtly affected by fibroblast reduction, few pups survived past postnatal day 11, suggesting an overall requirement for PDGFRα expressing fibroblasts.ConclusionsThese studies demonstrate the key role of fibroblasts in matrix production and cardiomyocyte cross-talk during mouse perinatal heart maturation and revealed that fibroblast-derived ECM may modulate cardiomyocyte maturation in vivo. Neonatal depletion of fibroblasts demonstrated that although hearts can tolerate reduced ECM composition, fibroblast loss eventually leads to perinatal death as the approach simultaneously reduced fibroblast populations in other organs.

Project description:The heart undergoes significant structural, metabolic, gene expression and functional alterations during the perinatal to postnatal transition. While recent studies have identified multiple epigenetic and transcriptional regulators of cardiac maturation, post-transcriptional mechanisms regulating this process remain poorly understood. Neddylation is a post-translational modification that conjugates a small ubiquitin-like protein, NEDD8, to protein substrates via an E1-E2-E3 enzymatic cascade. The goal of this study was to define the role of neddylation in perinatal cardiac development and cardiac maturation. Neddylation was inhibited in adult mouse hearts by cardiac-specific deletion of NAE1 gene, a regulatory subunit of NEDD8 E1 enzyme, or in neonatal cardiomyocytes (CMs) with a pharmacological neddylation inhibitor, MLN4924. The impact on cardiac transcriptome, metabolism, maturation and function was assessed. Mosaic deletion of NAE1 in ~40% neonatal CMs disrupted aspects of maturation, including transverse-tubule formation, cellular hypertrophy and fetal/adult isoform switching, whereas deletion of NAE1 in over 80% CMs led to rapid development of cardiomyopathy and heart failure. Transcriptome analysis demonstrated an association of metabolic derangement with immature cardiomyocyte signature. Biochemical, ultrastructural and metabolomics analyses confirmed downregulation of fatty acid and oxidative phosphorylation genes, deficits in fatty acid utilization, mitochondrial dysfunction, and significantly altered metabolic profiles in NAE1-deficient hearts or MLN4924-treated neonatal CMs. Mechanistically, we found that HIF1α, a transcription factor known to promote glycolysis and suppress oxidative metabolism, is a putative NEDD8 target. Inhibition of neddylation resulted in HIF1α accumulation and activation, which contributed to diminished fatty acid utilization. Taken together, we conclude that neddylation plays a crucial role in CM maturation and postnatal cardiac development through sustaining the glycolytic to oxidative metabolic switch in perinatal hearts.

Project description:Ventricular chambers are essential for the rhythmic contraction and relaxation that occurs in every hearbeat throughout life. Congenital abnormalities in ventricular chamber formation cause severe human heart defects. How the early trabecular meshwork of myocardial fibres forms and subsequently develops into mature chambers is still poorly understood. Here we show that Notch signalling first connects chamber endocardium and myocardium to sustain trabeculation and later coordinates ventricular patterning and compaction with coronary vessel development to give rise to the mature chamber via a temporal sequence of ligand signalling determined by the glycosyltransferase Manic Fringe (Mfng). The early endocardial expression of Mfng favours Dll4-Notch1 signalling, Which induces trabeculation in the developing ventricle.Ventricular maturation and compaction in turn require Mfng and Dll4 downregulation in the endocardium, Which allows myocardial Jag1- And Jag2- Signalling to Notch1 in this tissue.Timely and spatial perturbation of this signalling equilibrium severely disrupts heart chamber formation. Our results open a new research avenue into the pathogenesis of cardiomyopathies. Dll4 and Notch1 conditional KOs using Nfact1 and/or Tie2 driven Cre expression: RNA was isolated from pooled whole hearts of 8 (Nfact1) or 9 (Tie2) E9.5 embryos per replicate. Dll4flox;Nfatc1-Cre and WT siblings (4 KO and 4 WT replicates), Notch1flox;Nfatc1-Cre and WT siblings (3 KO and 2 WT replicates), Dll4flox;Tie2-Cre and WT siblings (3 KO and 3 WT replicates). Jag1, Jag2 and Jag1Jag2 conditional KOs using cTnT driven Cre expression: RNA was isolated from pooled heart ventricles of 4 E15.5 embryos per replicate. Jag1flox;cTnT-Cre and WT siblings (3 KO and 3 WT replicates), Jag2flox;cTnT-Cre and WT siblings (3 KO and 2 WT replicates). Jag1flox;jag2flox;cTnT-Cre and WT siblings (3 KO and 2 WT replicates). MFng Gain Of Function using Tie2 driven Cre expression: RNA was isolated from pooled heart ventricles of 4 E15.5 embryos per replicate. MFng;Tie2-Cre and WT siblings (4 GOF and 4 WT replicates). For Dll4, Noth1 and Jag1 KOs, libraries were prepared using the standard Illumina TrueSeq RNASeq library preparation kit and sequenced in a GAIIx Illumina sequencer using a 75bp single end elongation protocol. For Jag2 and Jag1Jag2 KOs and MFng GOF libraries were prepared prepared using the NEBNext Ultra RNA Library Prep Kit for Illumina and sequenced in a HiSeq2500 Illumina sequencer using a 61bp single end elongation protocol

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Wnt11 regulates cardiac chamber development and disease during perinatal maturation.

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Wnt11 regulates cardiac chamber development and disease during perinatal maturation.

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