Decision letter: Mechanically activated piezo channels modulate outflow tract valve development through the Yap1 and Klf2-Notch signaling axis

Mechanical forces are well known for modulating heart valve developmental programs. Yet, it is still unclear how genetic programs and mechanosensation interact during heart valve development. Here, we assessed the mechanosensitive pathways involved during zebrafish outflow tract (OFT) valve development in vivo. Our results show that the hippo effector Yap1, Klf2, and the Notch signaling pathway are all essential for OFT valve morphogenesis in response to mechanical forces, albeit active in different cell layers. Furthermore, we show that Piezo and TRP mechanosensitive channels are important factors modulating these pathways. In addition, live reporters reveal that Piezo controls Klf2 and Notch activity in the endothelium and Yap1 localization in the smooth muscle progenitors to coordinate OFT valve morphogenesis. Together, this work identifies a unique morphogenetic program during OFT valve formation and places Piezo as a central modulator of the cell response to forces in this process.

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Mechanically activated Piezo channels control outflow tract valve development through Yap1 and Klf2-Notch signaling axis

10.1101/529016 ◽

2019 ◽

Cited By ~ 1

Author(s):

Anne Laure Duchemin ◽

Hélène Vignes ◽

Julien Vermot

Keyword(s):

Notch Signaling ◽

Heart Valve ◽

Notch Signaling Pathway ◽

Outflow Tract ◽

Mechanical Forces ◽

Valve Development ◽

Signaling Axis ◽

Cell Layers ◽

Valve Formation

AbstractMechanical forces are well known for modulating heart valve developmental programs. Yet, it is still unclear how genetic programs and mechanosensation interact during heart valve development. Here, we assessed the mechanosensitive pathways involved during zebrafish outflow tract (OFT) valve development in vivo. Our results show that the hippo effector Yap1, Klf2, and the Notch signaling pathway are all essential for OFT valve morphogenesis in response to mechanical forces, albeit active in different cell layers. Furthermore, we show that Piezo and TRP mechanosensitive channels are essential for regulating these pathways. In addition, live reporters reveal that piezo controls Klf2 and Notch activity in the endothelium and Yap1 expression in the smooth muscle progenitors to coordinate OFT valve morphogenesis. Together, this work identifies a unique morphogenetic program during OFT valve formation and places Piezo as a central modulator of the cell response to forces in this process.

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RASSF1A disrupts the NOTCH signaling axis via SNURF/RNF4‐mediated ubiquitination of HES1

EMBO Reports ◽

10.15252/embr.202051287 ◽

2021 ◽

Author(s):

Angelos Papaspyropoulos ◽

Andriani Angelopoulou ◽

Ioanna Mourkioti ◽

Aikaterini Polyzou ◽

Daniela Pankova ◽

...

Keyword(s):

Notch Signaling ◽

Signaling Axis

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Piezo1 is required for outflow tract and aortic valve development.

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2020.03.013 ◽

2020 ◽

Vol 143 ◽

pp. 51-62 ◽

Cited By ~ 4

Author(s):

Adèle Faucherre ◽

Hamid Moha ou Maati ◽

Nathalie Nasr ◽

Amélie Pinard ◽

Alexis Theron ◽

...

Keyword(s):

Aortic Valve ◽

Outflow Tract ◽

Valve Development

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BMP4 is required in the anterior heart field and its derivatives for endocardial cushion remodeling, outflow tract septation, and semilunar valve development

Developmental Dynamics ◽

10.1002/dvdy.21743 ◽

2008 ◽

Vol 237 (11) ◽

pp. 3200-3209 ◽

Cited By ~ 85

Author(s):

David J. McCulley ◽

Ji-One Kang ◽

James F. Martin ◽

Brian L. Black

Keyword(s):

Outflow Tract ◽

Endocardial Cushion ◽

Semilunar Valve ◽

Valve Development ◽

Heart Field ◽

Anterior Heart Field

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Notch signaling in cardiac valve development and disease

Birth Defects Research Part A Clinical and Molecular Teratology ◽

10.1002/bdra.20815 ◽

2011 ◽

Vol 91 (6) ◽

pp. 449-459 ◽

Cited By ~ 50

Author(s):

Donal MacGrogan ◽

Luis Luna-Zurita ◽

José Luis de la Pompa

Keyword(s):

Notch Signaling ◽

Cardiac Valve ◽

Valve Development ◽

Cardiac Valve Development

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Abstract 13: Nkx2-5-notch Signaling Axis Regulates The Proliferation Of The Atrial Myocytes And Conduction System

Circulation Research ◽

10.1161/res.115.suppl_1.13 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Austin Nakano ◽

Yasuhiro Nakashima ◽

Diana A Yanez ◽

Marlin Touma ◽

Haruko Nakano ◽

...

Keyword(s):

Notch Signaling ◽

Notch Pathway ◽

Conduction System ◽

Cardiomyocyte Proliferation ◽

Tight Control ◽

Septal Defects ◽

Signaling Axis ◽

Human Mutation ◽

Early Lethality

Rationale: Tight control of cardiomyocyte proliferation is essential for the formation of four-chambered heart. Although human mutation of NKX2-5 is linked to septal defects and atrioventricular conduction abnormalities, early lethality and hemodynamic alteration in the mutant models have caused controversy as to whether Nkx2-5 regulates cardiomyocyte proliferation. Objective: In this study, we circumvented these limitations by atrial-restricted deletion of Nkx2-5. Method and Results: Atrial-specific Nkx2-5 mutants died shortly after birth with hyperplastic working myocytes and conduction system including two nodes and internodal tracts. Multicolor reporter analysis revealed that Nkx2-5-null cardiomyocytes displayed clonal proliferative activity throughout the atria, indicating the suppressive role of Nkx2-5 in the cardiomyocyte proliferation after chamber ballooning stages. Transcriptome analysis revealed that aberrant activation of Notch signaling underlies hyperproliferation of mutant cardiomyocytes, and forced activation of Notch signaling recapitulates hyperproliferation of working myocytes but not conduction system. Conclusion: Collectively, these data suggest that Nkx2-5 regulates proliferation of atrial working and conduction myocardium in coordination with Notch pathway.

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