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

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,...

Full description

Saved in:
Bibliographic Details
Published in:iScience 2020-03, Vol.23 (3), p.100959-100959, Article 100959
Main Authors: Yamak, Abir, Hu, Dongjian, Mittal, Nikhil, Buikema, Jan W., Ditta, Sheraz, Lutz, Pierre G., Moog-Lutz, Christel, Ellinor, Patrick T., Domian, Ibrahim J.
Format: Article
Language:English
Subjects:
Biological Sciences
Developmental Biology
Life Sciences
Molecular Biology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 Tgfβ/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. [Display omitted] •Flna removal partially rescues embryonic lethality of Asb2-heart-specific knockout•AHF-Asb2 knockouts harboring one Flna allele have double outlet right ventricle•Asb2-Flna regulate TGFβ-Smad2 signaling in the heart•Conserved role of Asb2 in heart morphogenesis between mice and humans Biological Sciences; Molecular Biology; Developmental Biology
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2020.100959