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dc.contributor.authorLittlejohn, Rodney
dc.date.accessioned2020-06-24T16:14:08Z
dc.date.available2020-06-24T16:14:08Z
dc.date.issued2020-07
dc.identifier.urihttp://hdl.handle.net/10675.2/623404
dc.descriptionRecord is embargoed until 6/22/2022
dc.description.abstractBackground. Early cardiac development is a tightly regulated process, involving spatiotemporal coordination of multiple signaling pathways and heterogenous cell populations, both generated de novo and externally sourced. While the roles of transcription, environmental, and epigenetic factors have all been studied extensively in the context of heart development, the roles of post-translational protein modification in regulating this process remain to be elucidated. NEDD8 (neural precursor cell expressed developmentally downregulated 8) is a novel ubiquitin-like protein modifier. Conjugation of NEDD8 to protein targets, a process termed neddylation, has been shown to regulate cell proliferation, cell signaling, and protein homeostasis, and play important roles in multiple physiological and pathological events. We have previously shown that neddylation is developmentally downregulated in the developing heart and is essential for mid-to-late gestational ventricular chamber maturation. However, whether and how neddylation regulates early cardiogenic events remains unknown. Methods and results. Mice with constitutive, cardiac progenitor cell-specific, cardiomyocyte- and vascular smooth muscle cell-specific deletion of NAE1, a regulatory subunit of the NEDD8-specific E1 activating enzyme, were created. Constitutive deletion of NAE1 led to early embryonic lethality before E9.5. Nkx2.5Cre-mediated deletion of NAE1 decreased neddylated proteins in the heart, disrupted normal cardiogenesis and resulted in embryonic lethality by embryonic day (E) 12.5 due to heart failure. Similarly, SM22αCre-driven deletion of NAE1 also caused cardiac failure and embryonic lethality by E13.5. The striking cardiac phenotypes were associated with myocardial hypoplasia, ventricular hypo-trabeculation, and pronounced endocardial and/or epicardial defects in both models. Unbiased transcriptomic analysis revealed dysregulated expression of genes associated with cardiomyocyte differentiation, proliferation, and maturation in NAE1-deficient hearts. Indeed, inhibition of neddylation disturbed cardiomyocyte proliferation, and myofibril assembly in vitro and in vivo. Moreover, defects in cardiomyocyte differentiation and maturation were linked to downregulation of Nkx2.5 and Mef2c, two key transcription factors regulating early cardiogenesis. Conclusion. Collectively, our findings demonstrate that neddylation in cardiac progenitor cells and cardiomyocytes is essential in the regulation of cardiogenesis in transgenic mouse models. Our results uncover a previously unknown role of post-translational modification in the regulation of cardiac development via potential roles in mediating cardiomyocyte proliferation, differentiation, and maturation.
dc.publisherAugusta University
dc.subjectCellular biology
dc.subjectMedicine
dc.subjectBiology
dc.subjectCardiomyocyte, development, differentiation, heart, post-translational modification, proliferation
dc.titleTHE ROLE OF NEDDYLATION IN EARLY CARDIAC DEVELOPMENT
dc.typedissertationen_US
dc.contributor.departmentDepartment of Cellular Biology and Anatomy
dc.language.rfc3066en
dc.date.updated2020-06-24T16:14:09Z
dc.description.advisorSu, Huabo
dc.description.degreePh.D.
dc.description.committeeWeintraub, Neal
dc.description.committeeStansfield, Brian
dc.description.committeeTang, Yaoliang
dc.description.committeeZhou, Jiliang
dc.embargo06/22/2022


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