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

Abir Yamak (1) , Dongjian Hu (1) , Nikhil Mittal (1) , Jan W Buikema (1) , Sheraz Ditta (1) , Pierre G Lutz (2) , Christel Moog-Lutz (1) , Patrick T Ellinor (1) , Ibrahim J Domian (1)

1 Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA
2 IPBS - Institut de pharmacologie et de biologie structurale

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 .Asb2 fl/fl and AHF-Cre.Asb2 fl/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 Tgfb/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.

Mots clés: Biological Sciences; Developmental Biology; Molecular Biology

Domaines: Sciences du Vivant [q-bio]

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-03021336⟩