Characterization of the Casz1-Dependent Mechanisms Essential for Cardiomyocyte Development Public Deposited

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  • March 19, 2019
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  • Dorr, Kerry
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • The heart is one of the first structures to form during development and is required for embryonic growth and survival. The four-chambered mammalian heart arises from a series of complex processes during embryonic development that includes the specification and differentiation of the different cardiac cell types within the heart, proliferation, and morphological movements of the early heart fields. Early development of the heart is governed by hyperplastic growth in which cardiac cells undergo mitogen-dependent activation during the G1-phase of the cell cycle. Though numerous growth factor signals have been shown to be required for cardiomyocyte proliferation, genetic studies have only identified a limited number of transcription factors that act to regulate the entry of cardiomyocytes into S-phase. Casz1 is an evolutionarily conserved transcription factor that is essential for heart development; however, there are vast deficiencies in our understanding of the mechanism by which Casz1 regulates aspects of cardiac development. Here we report that Casz1 is expressed in, and gives rise to, cardiomyocytes in the first and second heart fields. We show through the generation of a cardiac conditional null mutation that Casz1 is required for the proper development and growth of the cardiac chambers. We further demonstrate that Casz1 is essential for the proliferation of cardiomyocytes in both heart fields and that loss of Casz1 leads to severe cardiac hypoplasia, ventricular septal defects, and a decrease in cardiomyocyte cell number. Additionally, we report that the loss of Casz1 leads to a prolonged or arrested S-phase, a decrease in DNA synthesis, an increase in phosphorylated-Rb, and a concomitant decrease in the cardiac mitotic index. Taken together these studies establish a role for Casz1 in mammalian heart development and cardiomyocyte cell cycle progression.
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  • In Copyright
Advisor
  • Conlon, Frank
  • Qian, Li
  • Taylor, Joan
  • Wessels, Andy
  • Magnuson, Terry
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2015
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  • Chapel Hill, NC
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