Neural cell adhesion molecule is required for ventricular conduction system development

Delgado, Camila; Bu, Lei; Zhang, Jie; Liu, Fang-Yu; Sall, Joseph; Liang, Feng; Furley, Andrew J.; Fishman, Glenn I.

doi:10.1242/dev.199431

Cited by 14 publications

(13 citation statements)

References 70 publications

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“…In addition to mediating cell-cell interaction, NCAM-1 binding triggers activation of downstream signaling cascades, which have been extensively studied in the context of neural development. In Ncam-1 KO mice, the expression of several PF specific genes is downregulated [99]. Among them, some are involved in cellular conductance-such as Cx40 and Scn4b-whereas others, like ETV1, are necessary for conductive cell specification.…”

Section: Mouse Models With a Hypoplastic Vcsmentioning

confidence: 99%

New Insights into the Development and Morphogenesis of the Cardiac Purkinje Fiber Network: Linking Architecture and Function

Choquet¹,

Boulgakoff²,

Kelly³

et al. 2021

JCDD

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The rapid propagation of electrical activity through the ventricular conduction system (VCS) controls spatiotemporal contraction of the ventricles. Cardiac conduction defects or arrhythmias in humans are often associated with mutations in key cardiac transcription factors that have been shown to play important roles in VCS morphogenesis in mice. Understanding of the mechanisms of VCS development is thus crucial to decipher the etiology of conduction disturbances in adults. During embryogenesis, the VCS, consisting of the His bundle, bundle branches, and the distal Purkinje network, originates from two independent progenitor populations in the primary ring and the ventricular trabeculae. Differentiation into fast-conducting cardiomyocytes occurs progressively as ventricles develop to form a unique electrical pathway at late fetal stages. The objectives of this review are to highlight the structure–function relationship between VCS morphogenesis and conduction defects and to discuss recent data on the origin and development of the VCS with a focus on the distal Purkinje fiber network.

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Section: Mouse Models With a Hypoplastic Vcsmentioning

confidence: 99%

New Insights into the Development and Morphogenesis of the Cardiac Purkinje Fiber Network: Linking Architecture and Function

Choquet¹,

Boulgakoff²,

Kelly³

et al. 2021

JCDD

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show abstract

“…Semaphorin 3A may play an important role in the development of the cardiac conduction system ( 76 ). NCAM1 is also important for the development of the ventricular conduction system ( 77 ). Thus, there may be a synergistic effect between CMs and ECs in promoting development of the other cell type.…”

Section: Resultsmentioning

confidence: 99%

Tissue-embedded stretchable nanoelectronics reveal endothelial cell–mediated electrical maturation of human 3D cardiac microtissues

et al. 2023

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Clinical translation of stem cell therapies for heart disease requires electrical integration of transplanted cardiomyocytes. Generation of electrically matured human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) is critical for electrical integration. Here, we found that hiPSC-derived endothelial cells (hiPSC-ECs) promoted the expression of selected maturation markers in hiPSC-CMs. Using tissue-embedded stretchable mesh nanoelectronics, we achieved a long-term stable map of human three-dimensional (3D) cardiac microtissue electrical activity. The results revealed that hiPSC-ECs accelerated the electrical maturation of hiPSC-CMs in 3D cardiac microtissues. Machine learning–based pseudotime trajectory inference of cardiomyocyte electrical signals further revealed the electrical phenotypic transition path during development. Guided by the electrical recording data, single-cell RNA sequencing identified that hiPSC-ECs promoted cardiomyocyte subpopulations with a more mature phenotype, and multiple ligand-receptor interactions were up-regulated between hiPSC-ECs and hiPSC-CMs, revealing a coordinated multifactorial mechanism of hiPSC-CM electrical maturation. Collectively, these findings show that hiPSC-ECs drive hiPSC-CM electrical maturation via multiple intercellular pathways.

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“…22,23 For the LVOTO phenotype, a lead variant rs189203952 (MAF, 0.01 [OR, 2.4]; P =1.46×10 −8 ) is predicted to disrupt the motifs of 4 transcription factor binding sites known to participate in cardiac development 24–27 and is located in a region of open chromatin 250 bp distal to the promoter of SPAG9, a cytoskeletal adaptor protein and mediator of jun-kinase signaling 28 (Figure 2B). Three-dimensional chromatin data from mesodermal-related tissue suggests that rs78256848, which confers risk for CTD (MAF, 0.11 [OR, 1.4]; P =2.6×10 −8 ), physically interacts with NCAM1 ( P FDR =1.86×10 −27 ), a neural adhesion molecule recently recognized to play a role in aspects of cardiac development 29 (Figure S6). Reanalysis of the genomic-context surrounding the 4p16 risk locus for ASD 10 reveals that the lead variant rs1510798 (MAF, 0.23 [OR, 1.36]; P =4.6×10 −9 ) is linked with 2 variants predicted to disrupt motifs for AP-2 or NFAT factors in an enhancer active in mesendodermal precursors differentiated from human embryonic stem cells 30,31 (Figure 2C).…”

Section: Resultsmentioning

confidence: 99%

Oligogenic Architecture of Rare Noncoding Variants Distinguishes 4 Congenital Heart Disease Phenotypes

Aguirre

Jia

et al. 2023

Circ: Genomic and Precision Medicine

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Background: Congenital heart disease (CHD) is highly heritable, but the power to identify inherited risk has been limited to analyses of common variants in small cohorts. Methods: We performed reimputation of 4 CHD cohorts (n=55 342) to the TOPMed reference panel (freeze 5), permitting meta-analysis of 14 784 017 variants including 6 035 962 rare variants of high imputation quality as validated by whole genome sequencing. Results: Meta-analysis identified 16 novel loci, including 12 rare variants, which displayed moderate or large effect sizes (median odds ratio, 3.02) for 4 separate CHD categories. Analyses of chromatin structure link 13 of the genome-wide significant loci to key genes in cardiac development; rs373447426 (minor allele frequency, 0.003 [odds ratio, 3.37 for Conotruncal heart disease]; P =1.49×10 −8 ) is predicted to disrupt chromatin structure for 2 nearby genes BDH1 and DLG1 involved in Conotruncal development. A lead variant rs189203952 (minor allele frequency, 0.01 [odds ratio, 2.4 for left ventricular outflow tract obstruction]; P =1.46×10 − 8 ) is predicted to disrupt the binding sites of 4 transcription factors known to participate in cardiac development in the promoter of SPAG9 . A tissue-specific model of chromatin conformation suggests that common variant rs78256848 (minor allele frequency, 0.11 [odds ratio, 1.4 for Conotruncal heart disease]; P =2.6×10 − 8 ) physically interacts with NCAM1 ( P FDR =1.86×10 − 27 ), a neural adhesion molecule acting in cardiac development. Importantly, while each individual malformation displayed substantial heritability (observed h2 ranging from 0.26 for complex malformations to 0.37 for left ventricular outflow tract obstructive disease) the risk for different CHD malformations appeared to be separate, without genetic correlation measured by linkage disequilibrium score regression or regional colocalization. Conclusions: We describe a set of rare noncoding variants conferring significant risk for individual heart malformations which are linked to genes governing cardiac development. These results illustrate that the oligogenic basis of CHD and significant heritability may be linked to rare variants outside protein-coding regions conferring substantial risk for individual categories of cardiac malformation.

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Neural cell adhesion molecule is required for ventricular conduction system development

Cited by 14 publications

References 70 publications

New Insights into the Development and Morphogenesis of the Cardiac Purkinje Fiber Network: Linking Architecture and Function

New Insights into the Development and Morphogenesis of the Cardiac Purkinje Fiber Network: Linking Architecture and Function

Tissue-embedded stretchable nanoelectronics reveal endothelial cell–mediated electrical maturation of human 3D cardiac microtissues

Oligogenic Architecture of Rare Noncoding Variants Distinguishes 4 Congenital Heart Disease Phenotypes

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