Exploring the Role of Microtubule Binding Protein CENP-F in Cardiac Disease

Abstract

Cardiac development is a tightly controlled, step-wise process, as the heart is one of the first functional organs to develop. The major cell type of the heart is the cardiomyocyte and is known to be the work horse of the heart. Cardiac myocytes are very different than any other cell type, as they contain an infrastructure that allows for the involuntary contraction of the heart. Beginning at the anchoring of proteins at the z-disk, the sarcomere structure is gradually patterned. By adult, most cardiomyocytes are bi-nucleated, rod-shaped, and terminally differentiated. Although the microtubule network is a key organelle in the differentiation of every cell type, the role of microtubules in the heart, specifically in cardiac myocytes, has not been thoroughly explored. Genetic alteration of the microtubule network by Centromere Protein F (CENP-F) results in several structural and functional abnormalities in both humans and mice. Without CENP-F, mice hearts are dilated and undergo cardiac arrythmias. In isolated cardiomyocytes, calcium influx is disrupted, myocyte stiffness is greatly reduced, and major contractile components are significantly altered. As we observe changes in how CENP-F loss of function differs from cell to cell, our studies underlie the importance of understanding the role of CENP-F in the specific cell types of the organ of interest. Ultimately, these findings are novel as they lay the foundation for further studies on microtubules in cardiac development and health and, provide evidence for the potential impact of microtubule targeted chemotherapy treatments on heart disease.