Skip to Main content Skip to Navigation
Journal articles

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

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 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.
Document type :
Journal articles
Complete list of metadatas

https://hal-cnrs.archives-ouvertes.fr/hal-03019023
Contributor : Colette Orange <>
Submitted on : Monday, November 23, 2020 - 11:04:24 AM
Last modification on : Wednesday, December 16, 2020 - 12:12:04 PM

Links full text

Identifiers

Collections

Citation

Abir Yamak, Dongjian Hu, Nikhil Mittal, Jan W. Buikema, Sheraz Ditta, et al.. Loss of Asb2 Impairs Cardiomyocyte Differentiation and Leads to Congenital Double Outlet Right Ventricle. iScience, 2020, 23 (3), pp.100959. ⟨10.1016/j.isci.2020.100959⟩. ⟨hal-03019023⟩

Share

Metrics

Record views

10