Dokument

Summary:
Heart development is a tightly regulated process directed to control cardiomyocyte proliferation and differentiation. After birth, cardiomyocytes steadily lose the ability to proliferate and the heart growth is maintained by physiological hypertrophy and differentiation of the cardiomyocytes. Numerous transcription factors are involved in these processes and deregulation of them can lead to heart defects, heart failure and death. TEAD1 is a transcription factor that governs the expression of numerous muscle specific genes, however, little is known about the role of TEAD1 in cardiomyocytes. In order to study the role of TEAD1 in the heart, the present study aimed at analyzing TEAD1 function in cardiomyocytes based on loss- and gain-of-function studies to decipher postnatal TEAD1 regulated transcriptional networks. Our data indicate an essential role of TEAD1 for the cardiomyocyte differentiation and maturation in both, embryonic and postnatal hearts. Specifically, early deletion of Tead1 in cardiomyocytes is embryonically lethal and characterized by decreased cardiomyocyte proliferation and increased apoptosis. In addition, cardiomyocytes displayed delay in the development of myofibrils and intercalated discs. In contrast, mice harboring cardiomyocyte-specific Tead1 inactivation in postnatal stage die within 4 weeks after birth due to impaired cardiac function and heart dilatation. Moreover, postnatal Tead1-deficient cardiomyocytes showed decreased proliferation and increased apoptosis rate. In addition, in postnatal cardiomyocytes, Tead1 inactivation leads to diminished cardiomyocyte plasticity characterized by premature differentiation of cardiomyocytes. Importantly, the lethal heart phenotype of our conditional Tead1-deficient mice was rescued by cardiomyocyte-specific Tead1 overexpression. Transcriptome profiling of Tead1-deficient cardiomyocytes combined with genome-wide TEAD1 binding studies in wild-type cardiomyocytes revealed that TEAD1 regulates genes responsible for cardiomyocyte growth, differentiation, maturation, contraction, energy homeostasis, sarcomere and cytoskeleton organization. Taken together, these data indicate an important role of TEAD1 in embryonic and postnatal cardiomyocyte plasticity thus enabling proper physiological heart remodeling

Das Dokument ist im Internet frei zugänglich - Hinweise zu den Nutzungsrechten