Exogenous WNT5A and WNT11 proteins rescue CITED2 dysfunction in mouse embryonic stem cells and zebrafish morphants

João M.A. Santos; Leonardo Mendes-Silva; Vanessa Afonso; Gil Martins; Rui S.R. Machado; João A. Lopes; Leonor Cancela; Matthias E. Futschik; Agapios Sachinidis; Paulo Gavaia; José Bragança

doi:10.1038/s41419-019-1816-6

Exogenous WNT5A and WNT11 proteins rescue CITED2 dysfunction in mouse embryonic stem cells and zebrafish morphants

João M.A. Santos, Leonardo Mendes-Silva, Vanessa Afonso, Gil Martins, Rui S.R. Machado, João A. Lopes, Leonor Cancela, Matthias E. Futschik, Agapios Sachinidis, Paulo Gavaia, José Bragança^*

^*Corresponding author for this work

School of Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

AbstractMutations and inadequate methylation profiles of CITED2 are associated with human congenital heart disease (CHD). In mouse, Cited2 is necessary for embryogenesis, particularly for heart development, and its depletion in embryonic stem cells (ESC) impairs cardiac differentiation. We have now determined that Cited2 depletion in ESC affects the expression of transcription factors and cardiopoietic genes involved in early mesoderm and cardiac specification. Interestingly, the supplementation of the secretome prepared from ESC overexpressing CITED2, during the onset of differentiation, rescued the cardiogenic defects of Cited2-depleted ESC. In addition, we demonstrate that the proteins WNT5A and WNT11 held the potential for rescue. We also validated the zebrafish as a model to investigate cited2 function during development. Indeed, the microinjection of morpholinos targeting cited2 transcripts caused developmental defects recapitulating those of mice knockout models, including the increased propensity for cardiac defects and severe death rate. Importantly, the co-injection of anti-cited2 morpholinos with either CITED2 or WNT5A and WNT11 recombinant proteins corrected the developmental defects of Cited2-morphants. This study argues that defects caused by the dysfunction of Cited2 at early stages of development, including heart anomalies, may be remediable by supplementation of exogenous molecules, offering the opportunity to develop novel therapeutic strategies aiming to prevent CHD.

Original language	English
Number of pages	0
Journal	Cell Death & Disease
Volume	10
Issue number	8
DOIs	https://doi.org/10.1038/s41419-019-1816-6
Publication status	E-pub ahead of print - 5 Aug 2019

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Santos, J. M. A., Mendes-Silva, L., Afonso, V., Martins, G., Machado, R. S. R., Lopes, J. A., Cancela, L., Futschik, M. E., Sachinidis, A., Gavaia, P., & Bragança, J. (2019). Exogenous WNT5A and WNT11 proteins rescue CITED2 dysfunction in mouse embryonic stem cells and zebrafish morphants. Cell Death & Disease, 10(8). Advance online publication. https://doi.org/10.1038/s41419-019-1816-6

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title = "Exogenous WNT5A and WNT11 proteins rescue CITED2 dysfunction in mouse embryonic stem cells and zebrafish morphants",

abstract = "AbstractMutations and inadequate methylation profiles of CITED2 are associated with human congenital heart disease (CHD). In mouse, Cited2 is necessary for embryogenesis, particularly for heart development, and its depletion in embryonic stem cells (ESC) impairs cardiac differentiation. We have now determined that Cited2 depletion in ESC affects the expression of transcription factors and cardiopoietic genes involved in early mesoderm and cardiac specification. Interestingly, the supplementation of the secretome prepared from ESC overexpressing CITED2, during the onset of differentiation, rescued the cardiogenic defects of Cited2-depleted ESC. In addition, we demonstrate that the proteins WNT5A and WNT11 held the potential for rescue. We also validated the zebrafish as a model to investigate cited2 function during development. Indeed, the microinjection of morpholinos targeting cited2 transcripts caused developmental defects recapitulating those of mice knockout models, including the increased propensity for cardiac defects and severe death rate. Importantly, the co-injection of anti-cited2 morpholinos with either CITED2 or WNT5A and WNT11 recombinant proteins corrected the developmental defects of Cited2-morphants. This study argues that defects caused by the dysfunction of Cited2 at early stages of development, including heart anomalies, may be remediable by supplementation of exogenous molecules, offering the opportunity to develop novel therapeutic strategies aiming to prevent CHD.",

author = "Santos, {Jo{\~a}o M.A.} and Leonardo Mendes-Silva and Vanessa Afonso and Gil Martins and Machado, {Rui S.R.} and Lopes, {Jo{\~a}o A.} and Leonor Cancela and Futschik, {Matthias E.} and Agapios Sachinidis and Paulo Gavaia and Jos{\'e} Bragan{\c c}a",

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doi = "10.1038/s41419-019-1816-6",

language = "English",

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T1 - Exogenous WNT5A and WNT11 proteins rescue CITED2 dysfunction in mouse embryonic stem cells and zebrafish morphants

AU - Santos, João M.A.

AU - Mendes-Silva, Leonardo

AU - Afonso, Vanessa

AU - Martins, Gil

AU - Machado, Rui S.R.

AU - Lopes, João A.

AU - Cancela, Leonor

AU - Futschik, Matthias E.

AU - Sachinidis, Agapios

AU - Gavaia, Paulo

AU - Bragança, José

PY - 2019/8/5

Y1 - 2019/8/5

N2 - AbstractMutations and inadequate methylation profiles of CITED2 are associated with human congenital heart disease (CHD). In mouse, Cited2 is necessary for embryogenesis, particularly for heart development, and its depletion in embryonic stem cells (ESC) impairs cardiac differentiation. We have now determined that Cited2 depletion in ESC affects the expression of transcription factors and cardiopoietic genes involved in early mesoderm and cardiac specification. Interestingly, the supplementation of the secretome prepared from ESC overexpressing CITED2, during the onset of differentiation, rescued the cardiogenic defects of Cited2-depleted ESC. In addition, we demonstrate that the proteins WNT5A and WNT11 held the potential for rescue. We also validated the zebrafish as a model to investigate cited2 function during development. Indeed, the microinjection of morpholinos targeting cited2 transcripts caused developmental defects recapitulating those of mice knockout models, including the increased propensity for cardiac defects and severe death rate. Importantly, the co-injection of anti-cited2 morpholinos with either CITED2 or WNT5A and WNT11 recombinant proteins corrected the developmental defects of Cited2-morphants. This study argues that defects caused by the dysfunction of Cited2 at early stages of development, including heart anomalies, may be remediable by supplementation of exogenous molecules, offering the opportunity to develop novel therapeutic strategies aiming to prevent CHD.

AB - AbstractMutations and inadequate methylation profiles of CITED2 are associated with human congenital heart disease (CHD). In mouse, Cited2 is necessary for embryogenesis, particularly for heart development, and its depletion in embryonic stem cells (ESC) impairs cardiac differentiation. We have now determined that Cited2 depletion in ESC affects the expression of transcription factors and cardiopoietic genes involved in early mesoderm and cardiac specification. Interestingly, the supplementation of the secretome prepared from ESC overexpressing CITED2, during the onset of differentiation, rescued the cardiogenic defects of Cited2-depleted ESC. In addition, we demonstrate that the proteins WNT5A and WNT11 held the potential for rescue. We also validated the zebrafish as a model to investigate cited2 function during development. Indeed, the microinjection of morpholinos targeting cited2 transcripts caused developmental defects recapitulating those of mice knockout models, including the increased propensity for cardiac defects and severe death rate. Importantly, the co-injection of anti-cited2 morpholinos with either CITED2 or WNT5A and WNT11 recombinant proteins corrected the developmental defects of Cited2-morphants. This study argues that defects caused by the dysfunction of Cited2 at early stages of development, including heart anomalies, may be remediable by supplementation of exogenous molecules, offering the opportunity to develop novel therapeutic strategies aiming to prevent CHD.

U2 - 10.1038/s41419-019-1816-6

DO - 10.1038/s41419-019-1816-6

M3 - Article

SN - 2041-4889

VL - 10

JO - Cell Death & Disease

JF - Cell Death & Disease

IS - 8

ER -

Exogenous WNT5A and WNT11 proteins rescue CITED2 dysfunction in mouse embryonic stem cells and zebrafish morphants

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