Universität zu Köln

Santos, Joao M. A., Mendes-Silva, Leonardo, Afonso, Vanessa, Martins, Gil, Machado, Rui S. R., Lopes, Joao A., Cancela, Leonor, Futschik, Matthias E., Sachinidis, Agapios, Gavaia, Paulo ORCID: 0000-0002-9582-1957 and Braganca, Jose ORCID: 0000-0001-9566-400X (2019). Exogenous WNT5A and WNT11 proteins rescue CITED2 dysfunction in mouse embryonic stem cells and zebrafish morphants. Cell Death Dis., 10. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-4889

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Abstract

Mutations 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Santos, Joao M. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mendes-Silva, Leonardo UNSPECIFIED UNSPECIFIED UNSPECIFIED Afonso, Vanessa UNSPECIFIED UNSPECIFIED UNSPECIFIED Martins, Gil UNSPECIFIED UNSPECIFIED UNSPECIFIED Machado, Rui S. R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lopes, Joao A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cancela, Leonor UNSPECIFIED UNSPECIFIED UNSPECIFIED Futschik, Matthias E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sachinidis, Agapios UNSPECIFIED UNSPECIFIED UNSPECIFIED Gavaia, Paulo UNSPECIFIED orcid.org/0000-0002-9582-1957 UNSPECIFIED Braganca, Jose UNSPECIFIED orcid.org/0000-0001-9566-400X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-144835
DOI:	10.1038/s41419-019-1816-6
Journal or Publication Title:	Cell Death Dis.
Volume:	10
Date:	2019
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2041-4889
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HEART DEVELOPMENT; DEFECTS; AXIS; DIFFERENTIATION; MUTATIONS; GENETICS Multiple languages Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14483