2. Academic Validation
  3. Loss of Asb2 Impairs Cardiomyocyte Differentiation and Leads to Congenital Double Outlet Right Ventricle

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

  • iScience. 2020 Mar 27;23(3):100959. doi: 10.1016/j.isci.2020.100959.
Abir Yamak 1,  Dongjian Hu 2,  Nikhil Mittal 3,  Jan W Buikema 4,  Sheraz Ditta 5,  Pierre G Lutz 6,  Christel Moog-Lutz 6,  Patrick T Ellinor 7,  Ibrahim J Domian 8
Affiliations

Affiliations

  • 1 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: [email protected].
  • 2 Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, CPZN3200, Boston, MA 02114, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
  • 3 Harvard Medical School, Boston, MA 02115, USA; Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, CPZN3200, Boston, MA 02114, USA.
  • 4 Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, CPZN3200, Boston, MA 02114, USA; University Medical Center Utrecht, 3584 CX Utrecht, Netherlands.
  • 5 Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, CPZN3200, Boston, MA 02114, USA; Department of Pharmaceutical Sciences, Utrecht University, 3512 JE Utrecht, Netherlands.
  • 6 Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France.
  • 7 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.
  • 8 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: [email protected].
PMID: 32179481 DOI: 10.1016/j.isci.2020.100959
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.

Keywords

Biological Sciences; Developmental Biology; Molecular Biology.

Figures