| First Author | Yamak A | Year | 2020 |
| Journal | iScience | Volume | 23 |
| Issue | 3 | Pages | 100959 |
| PubMed ID | 32179481 | Mgi Jnum | J:306640 |
| Mgi Id | MGI:6717247 | Doi | 10.1016/j.isci.2020.100959 |
| Citation | Yamak A, et al. (2020) Loss of Asb2 Impairs Cardiomyocyte Differentiation and Leads to Congenital Double Outlet Right Ventricle. iScience 23(3):100959 |
| abstractText | 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 Tgfbeta/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. |
