Intercalated discs (ICDs) are cardiac-specific structures located at the longitudinal termini of cardiomyocytes. Classically, the functions assigned to ICDs include mechanical and electrical communications among adjacent cardiomyocytes. More recently, it has been increasingly realized that ICDs also function in signal transduction and regulation of the surface expression of ion channels. Accordingly, defects of ICD components are shown to cause a number of human cardiac diseases and changes of ICDs are associated with cardiomyopathy, arrhythmias, and heart failure. The expansion of our knowledge about the development, function and maintenance of ICDs are promoted by identification, cataloging and characterization of the molecular components of the ICDs. In this thesis, I characterize a family of Xin repeat-containing proteins, which are striated muscle-specific and localized to the ICDs in the cardiomyocytes. This thesis provides novel insights into the mechanism of the formation, maintenance and functions of ICDs.
Our previous studies showed that the Xin repeat-containing proteins play critical role in cardiac morphogenesis and cardiac function. Knocking down the Xin in chicken embryo collapses the wall of developing heart chambers and leads to abnormal cardiac morphogenesis. In mammals, a pair of paralogous genes, Xinα and Xinβ , exists. Ablation of the mouse Xinα ( mXinα) does not affect heart development. Instead, the mXinα-deficient mice show adult late-onset cardiac hypertrophy and cardiomyopathy with conduction defects. The ICD structural defects in mXinα-null mice occur between 1 and 3 months of age and progressively worsen with aging. The mXinα-deficient hearts up-regulate mXinβ, suggesting a partial compensatory role of mXinβ.
In this thesis, I focus on two questions. First, what are the molecular mechanisms of mXinα's functions that account for the observed phenotypes in the mXinα-deficient hearts? And second, what are the functions of mXinβ? Through biochemical methods and electron microscopy, I demonstrated that mXinα binds and bundles actin filaments. In addition, a direct interaction between mXinα and the adherens junction protein β-catenin facilitates mXinα's interaction with the actin filaments. Based on this in vitro characterization of mXinα, we proposed that mXinα may act as a direct link between the adherens junctions and actin cytoskeleton, thus providing an important means to strengthening the intercellular adhesion at the ICDs. To characterize mXinβ's roles, I generated and characterized mXinβ-knockout mice. I showed that complete loss of mXinβ leads to cardiac morphological defects, diastolic dysfunction and heart failure, which lead to severe growth retardation and early postnatal lethality. I also showed that mXinβ might be involved in a number of cell signaling pathways and provide multiple lines of evidence to support mXinβ's roles in the formation of ICDs.
In summary, this thesis provides novel insights into the specialization of the adherens junctions at the ICDs to withstand the contractile forces, and the molecular mechanisms for the establishment, maintenance and function of ICDs. The knowledge gained from the roles of Xin proteins in cardiac development and function will likely provide new insights for improved therapeutic strategies for human cardiomyopathy, arrhythmias and heart failure.
|Advisor:||Lin, Jim J.-C.|
|Commitee:||Rubenstein, Peter A., Slusarski, Diane C., Stipp, Christopher S., Wu, Chun-Fang|
|School:||The University of Iowa|
|School Location:||United States -- Iowa|
|Source:||DAI-B 74/10(E), Dissertation Abstracts International|
|Subjects:||Cellular biology, Developmental biology|
|Keywords:||Cardiac development, Cardiomyocytes, Intercalated discs, Xin repeat-containing proteins|
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