The heart is the first organ to form and the beating heart is essential for survival by distributing the nutrients and oxygen within the embryo. At an early stage of its development, the heart is acting like a pump thanks to the cardiomyocytes, the specialized heart muscle cells able to contract. Researchers at the Institute of Pharmacology and Structural Biology (IPBS - CNRS/Université Toulouse III - Paul Sabatier) uncover a novel key step of cardiac cell differentiation. This study is published in Circulation Research, the journal of the American Heart Association, on January 26, 2018.
ASB2α-induced degradation of filamin A (in green) in the developing mouse heart (cardiomyocytes labeled in magenta and blue) is essential to build the contractile apparatus of cardiomyocytes and thus, for heartbeats.
© Arnaud Métais, Pierre Lutz & Christel Lutz (IPBS/CNRS-Université Paul Sabatier)
In a work dedicated to the understanding of the molecular mechanisms dysregulated in leukemia, researchers of P. Lutz lab identified the ASB2α protein and showed that this protein is involved in controlled proteolysis of protein targets by the proteasome. Indeed, ASB2α triggers degradation of the actin-binding protein filamins, thereby regulating functions of blood cells. The researchers have now showed that the primary function of ASB2α during embryogenesis is to control filamin A degradation in embryonic cardiomyocytes and that this is crucial for mouse embryos.
In humans, filamin A mutations are known to be the cause of the most common genetic heart valvular disorder and filamin A was previously reported to be required for heart function. This study now reveal that the timely controlled removal of filamin A ensures critical functions in differentiating cardiac muscle cells. Filamin A degradation is necessary to modify the actin cytoskeleton organization and properties in order to build the sarcomere, and thus for heartbeats. Furthermore, the researchers found that filamin A degradation marks an intermediate stage between cardiac progenitors and mature cardiomyocytes named immature cardiomyocytes. Overall, the data uncover an unsuspected role for the ASB2α-filamin A axis in heart development.
Cardiovascular diseases are the leading cause of death in developed countries. Of note, the adult mammalian heart cannot efficiently generate new cardiac muscle cells in response to injury. Importantly, the cellular processes and regulatory mechanisms involved in heart growth and development during embryogenesis can be exploited to repair the injured adult heart. In this context, identifying key molecules controlling cardiac cell differentiation is a major challenge for regenerative medicine. Thus, the findings have potential for translation into the clinics as they may help developing novel strategies for cardiomyocyte generation for heart regenerative purposes.
Arnaud Métais, Isabelle Lamsoul, Armelle Melet, Sandrine Uttenweiler-Joseph, Renaud Poincloux, Sonia Stefanovic, Amélie Valière, Anne Gonzalez de Peredo, Alexandre Stella, Odile Burlet-Schiltz, Stéphane Zaffran, Pierre G. Lutz* and Christel Moog-Lutz*. The Asb2α-filamin A axis is essential for actin cytoskeleton remodeling during heart development. Circulation Research. Published ahead of print January 26, 2018
This work was performed in collaboration with the groups of Dr. Odile Burlet-Schiltz (IPBS, CNRS/Université de Toulouse) and Dr. Stéphane Zaffran (Université d’Aix Marseille, INSERM U1251, Centre de Génétique Médicale de Marseille).