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Publication : Asb2α-Filamin A Axis Is Essential for Actin Cytoskeleton Remodeling During Heart Development.

First Author  Métais A Year  2018
Journal  Circ Res Volume  122
Issue  6 Pages  e34-e48
PubMed ID  29374072 Mgi Jnum  J:306706
Mgi Id  MGI:6718235 Doi  10.1161/CIRCRESAHA.117.312015
Citation  Metais A, et al. (2018) Asb2alpha-Filamin A Axis Is Essential for Actin Cytoskeleton Remodeling During Heart Development. Circ Res 122(6):e34-e48
abstractText  RATIONALE: Heart development involves differentiation of cardiac progenitors and assembly of the contractile sarcomere apparatus of cardiomyocytes. However, little is known about the mechanisms that regulate actin cytoskeleton remodeling during cardiac cell differentiation. OBJECTIVE: The Asb2alpha (Ankyrin repeat-containing protein with a suppressor of cytokine signaling box 2) CRL5 (cullin 5 RING E3 ubiquitin ligase) triggers polyubiquitylation and subsequent degradation by the proteasome of FLNs (filamins). Here, we investigate the role of Asb2alpha in heart development and its mechanisms of action. METHODS AND RESULTS: Using Asb2 knockout embryos, we show that Asb2 is an essential gene, critical to heart morphogenesis and function, although its loss does not interfere with the overall patterning of the embryonic heart tube. We show that the Asb2alpha E3 ubiquitin ligase controls Flna stability in immature cardiomyocytes. Importantly, Asb2alpha-mediated degradation of the actin-binding protein Flna marks a previously unrecognized intermediate step in cardiac cell differentiation characterized by cell shape changes and actin cytoskeleton remodeling. We further establish that in the absence of Asb2alpha, myofibrils are disorganized and that heartbeats are inefficient, leading to embryonic lethality in mice. CONCLUSIONS: These findings identify Asb2alpha as an unsuspected key regulator of cardiac cell differentiation and shed light on the molecular and cellular mechanisms determining the onset of myocardial cell architecture and its link with early cardiac function. Although Flna is known to play roles in cytoskeleton organization and to be required for heart function, this study now reveals that its degradation mediated by Asb2alpha ensures essential functions in differentiating cardiac progenitors.
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