Mechanosensitive Notch-Dll4 and Klf2-Wnt9 signaling pathways intersect in guiding valvulogenesis in zebrafish

Paolini, Alessio; Fontana, Federica; Pham, Van-Cuong; Rödel, Claudia Jasmin; Abdelilah‐Seyfried, Salim

doi:10.1016/j.celrep.2021.109782

Cited by 28 publications

(24 citation statements)

References 52 publications

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“…We demonstrated that Wnt/β-catenin signaling reporter line exhibited disrupted expression pattern, while Notch-activated cells in the corresponding reporter line didn’t show any effect. The different activities of Notch and Wnt/β-catenin observed in cfdp1 mutant hearts indicate the composition of two different cell subsets, in accordance to previously reported Notch-activated luminal AV cells and Wnt/β-catenin-activated abluminal AV cells during valve formation 39,69 . Moreover, it has been shown that although Notch and Wnt signaling intersect in order to promote the TCF-positive endocardial cells ingression into cardiac jelly during valvulogenesis, inhibition of Erk5-Klf2 pathway impairs canonical Wnt signaling without affecting Notch nor Dll4 activation in atrioventricular endocardial cells, confirming that these pathways are regulated independently 69 .…”

Section: Discussionsupporting

confidence: 90%

Cfdp1 is Essential for Cardiac Development and Function

Giardoglou

Deloukas

George

et al. 2022

Preprint

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Cardiovascular diseases (CVDs) are the prevalent cause of mortality worldwide and account for the most common noncommunicable disease. CVDs describe a wide spectrum of disorders affecting the proper function, physiology and morphogenesis of the heart and blood vessels. The risk of developing cardiovascular diseases is modulated by a combination of environmental and genetic effectors. Thus, it is highly important to identify candidate genes and elucidate their role in the manifestation of the disease. Large-scale human studies have revealed the implication of Craniofacial Development Protein 1 (CFDP1) in coronary artery disease (CAD). CFDP1 belongs to the evolutionary conserved Bucentaur (BCNT) family and up to date, its function and mechanism of action in Cardiovascular Development is still unclear. In this study, we utilize zebrafish to investigate the role of cfdp1 in the developing heart due to the high genomic homology, similarity in heart physiology and the ease of experimentally manipulation. We showed that cfdp1 is expressed during development and at 120 hours post fertilization its expression is restricted to the region of the heart and the head. We then generated a cfdp1-null zebrafish line using CRISPR-Cas9 system which led to a lethal phenotype since knockout embryos do not reach adulthood. cfdp1-/- embryos develop arrhythmic hearts and defective cardiac performance exhibiting statistically significant differences in heart features including End Diastolic Volume, Cardiac Output, Ejection Fraction and Stroke Volume. Myocardial trabeculation is also impaired in cfdp1-/- embryonic hearts, implying its regulatory role also in this developmental process. Findings from both knockdown and knockout experiments showed that abrogation of cfdp1 leads to downregulation of Wnt signaling in embryonic hearts during valve development but without affecting Notch activation in this process.

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Section: Discussionsupporting

confidence: 90%

Cfdp1 is Essential for Cardiac Development and Function

Giardoglou

Deloukas

George

et al. 2022

Preprint

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“…A second cleavage by γ-secretase then releases the intracellular domain, NICD, which forms a complex with a DNA-binding transcription factor and a co-activator to regulate transcription of target genes. In many developmental processes, Notch activation occurs contemporaneously with morphological changes which could modulate pathway activity so that signaling and tissue rearrangements are coordinated ( Paolini et al, 2021 ; Han et al, 2021 ; Engel-Pizcueta and Pujades, 2021 ; Lloyd-Lewis et al, 2019 ). For example, cell shape or tension changes in the neighboring cells could impact on the forces exerted on the receptor to alter the amount of cleavage ( Shaya et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Notch-dependent and -independent transcription are modulated by tissue movements at gastrulation

Falo‐Sanjuan

Bray

2022

eLife

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Cells sense and integrate external information from diverse sources that include mechanical cues. Shaping of tissues during development may thus require coordination between mechanical forces from morphogenesis and cell-cell signalling to confer appropriate changes in gene expression. By live-imaging Notch-induced transcription in real time we have discovered that morphogenetic movements during Drosophila gastrulation bring about an increase in activity-levels of a Notch responsive enhancer. Mutations that disrupt the timing of gastrulation resulted in concomitant delays in transcription up-regulation that correlated with the start of mesoderm invagination. As a similar gastrulation-induced effect was detected when transcription was elicited by the intracellular domain NICD, it cannot be attributed to forces exerted on Notch receptor activation. A Notch independent vnd enhancer also exhibited a modest gastrulation-induced activity increase in the same stripe of cells. Together, these observations argue that gastrulation-associated forces act on the nucleus to modulate transcription levels. This regulation was uncoupled when the complex linking the nucleoskeleton and cytoskeleton (LINC) was disrupted, indicating a likely conduit. We propose that the coupling between tissue level mechanics, arising from gastrulation, and enhancer activity represents a general mechanism for ensuring correct tissue specification during development and that Notch dependent enhancers are highly sensitive to this regulation.

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“…Klf2a has been shown to act in parallel with Notch to inhibit Flt4, a protein that is thought to be expressed in abluminal cells of zebrafish superior AV valves and strongly expressed in cells undergoing EndoMT in mouse AV valves [ 55 ]. Meanwhile, mechanosensitive Notch-Delta-like-4 and Erk5-Klf2-Wnt9a signaling pathways act together to regulate early zebrafish superior AV valve formation [ 62 ]. Specifically, Notch-mediated lateral inhibition between endocardial cells is thought to single out Delta-like-4-positive endocardial cells, which acquire competence to respond to Wnt9a.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, Notch-mediated lateral inhibition between endocardial cells is thought to single out Delta-like-4-positive endocardial cells, which acquire competence to respond to Wnt9a. Concurrently, Wnt9a is produced downstream of Klf2, leading to the ingression of Delta-like-4-positive endocardial cells [ 62 ]. Finally, Klf2-Wnt/β-catenin signaling is thought to limit mesenchymal cell proliferation in mouse valves during remodeling stages [ 17 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies in zebrafish have shown that cardiac forces regulate EndoMT during the early cell migration stage of valve formation [11,46,[60][61][62], but whether they play a role in later stages of valve development is unclear. Here, we focus on valves growing under abnormal flow conditions that have managed to bypass early developmental defects.…”

Section: Mechanotransduction During Av Valve Delaminationmentioning

confidence: 99%

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Cardiac forces regulate zebrafish heart valve delamination by modulating Nfat signaling

et al. 2022

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In the clinic, most cases of congenital heart valve defects are thought to arise through errors that occur after the endothelial–mesenchymal transition (EndoMT) stage of valve development. Although mechanical forces caused by heartbeat are essential modulators of cardiovascular development, their role in these later developmental events is poorly understood. To address this question, we used the zebrafish superior atrioventricular valve (AV) as a model. We found that cellularized cushions of the superior atrioventricular canal (AVC) morph into valve leaflets via mesenchymal–endothelial transition (MEndoT) and tissue sheet delamination. Defects in delamination result in thickened, hyperplastic valves, and reduced heart function. Mechanical, chemical, and genetic perturbation of cardiac forces showed that mechanical stimuli are important regulators of valve delamination. Mechanistically, we show that forces modulate Nfatc activity to control delamination. Together, our results establish the cellular and molecular signature of cardiac valve delamination in vivo and demonstrate the continuous regulatory role of mechanical forces and blood flow during valve formation.

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Mechanosensitive Notch-Dll4 and Klf2-Wnt9 signaling pathways intersect in guiding valvulogenesis in zebrafish

Cited by 28 publications

References 52 publications

Cfdp1 is Essential for Cardiac Development and Function

Cfdp1 is Essential for Cardiac Development and Function

Notch-dependent and -independent transcription are modulated by tissue movements at gastrulation

Cardiac forces regulate zebrafish heart valve delamination by modulating Nfat signaling

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