Loss of Asb2 Impairs Cardiomyocyte Differentiation and Leads to Congenital Double Outlet Right Ventricle.

Yamak, Abir; Hu, Dongjian; Mittal, Nikhil; Buikema, Jan W; Ditta, Sheraz; Lutz, Pierre G; Moog-Lutz, Christel; Ellinor, Patrick T; Domian, Ibrahim J

Yamak, Abir; Hu, Dongjian; Mittal, Nikhil; Buikema, Jan W; Ditta, Sheraz; Lutz, Pierre G; Moog-Lutz, Christel; Ellinor, Patrick T; Domian, Ibrahim J.

Afiliação

Yamak A; Harvard Medical School, Boston, MA 02115, USA; Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, CPZN3200, Boston, MA 02114, USA; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: fyamak@mgh.harvar
Hu D; Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, CPZN3200, Boston, MA 02114, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
Mittal N; Harvard Medical School, Boston, MA 02115, USA; Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, CPZN3200, Boston, MA 02114, USA.
Buikema JW; Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, CPZN3200, Boston, MA 02114, USA; University Medical Center Utrecht, 3584 CX Utrecht, Netherlands.
Ditta S; Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, CPZN3200, Boston, MA 02114, USA; Department of Pharmaceutical Sciences, Utrecht University, 3512 JE Utrecht, Netherlands.
Lutz PG; Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France.
Moog-Lutz C; Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France.
Ellinor PT; Harvard Medical School, Boston, MA 02115, USA; Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, CPZN3200, Boston, MA 02114, USA; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Domian IJ; Harvard Medical School, Boston, MA 02115, USA; Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, CPZN3200, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: idomian@mgh.harvard.edu.

iScience ; 23(3): 100959, 2020 Mar 27.

Article em En | MEDLINE | ID: mdl-32179481

ABSTRACT

ABSTRACT

Defining the pathways that control cardiac development facilitates understanding the pathogenesis of congenital heart disease. Herein, we identify enrichment of a Cullin5 Ub ligase key subunit, Asb2, in myocardial progenitors and differentiated cardiomyocytes. Using two conditional murine knockouts, Nkx+/Cre.Asb2fl/fl and AHF-Cre.Asb2fl/fl, and tissue clarifying technique, we reveal Asb2 requirement for embryonic survival and complete heart looping. Deletion of Asb2 results in upregulation of its target Filamin A (Flna), and concurrent Flna deletion partially rescues embryonic lethality. Conditional AHF-Cre.Asb2 knockouts harboring one Flna allele have double outlet right ventricle (DORV), which is rescued by biallelic Flna excision. Transcriptomic and immunofluorescence analyses identify Tgfß/Smad as downstream targets of Asb2/Flna. Finally, using CRISPR/Cas9 genome editing, we demonstrate Asb2 requirement for human cardiomyocyte differentiation suggesting a conserved mechanism between mice and humans. Collectively, our study provides deeper mechanistic understanding of the role of the ubiquitin proteasome system in cardiac development and suggests a previously unidentified murine model for DORV.

Palavras-chave

Biological Sciences; Developmental Biology; Molecular Biology

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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: IScience Ano de publicação: 2020 Tipo de documento: Article