Date of Award

3-24-2026

Embargo Period

4-13-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Additional Department

Molecular and Cellular Biology and Pathobiology

College

College of Graduate Studies

First Advisor

Andy Wessels

Second Advisor

Russell Norris

Third Advisor

Robin Muise-Helmericks

Fourth Advisor

Amy Bradshaw

Fifth Advisor

Amy Engevik

Abstract

Approximately 40,000 babies born each year in the U.S. have a congenital heart defect (CHD). However, only a small percentage of CHDs has a known genetic cause, highlighting the need for research surrounding heart development and the pathogenesis of CHDs. Heart development research aims to elucidate the precise coordination of gene expression and cell signaling with the goal of advancing prevention and treatment methods. During heart development, cells from several origins play a crucial role. This includes cells derived from the endocardium, epicardium, cardiac neural crest, and second heart field. Previous studies have revealed that the transcription factor, SOX9, is essential for regulating a number of cellular events in valvuloseptal development. SOX9 interacts with other SOX family members, including SOX6, to cooperatively regulate gene expression. Although SOX6 has documented roles in the postnatal heart, the work in this dissertation is the first to examine its role in the embryonic mouse heart. We utilize lineage-specific cre-recombinase mouse models, immunofluorescent detection methods, and RNAscope analyses to examine the expression of SOX6 and other SOX family members and the effects of endothelial/endocardial-specific deletion of Sox6. These expression studies reveal that SOX6 is expressed in each cell lineage contributing to the formation of the heart. Further experiments comparing Sox5 mRNA, Sox6 mRNA, and SOX9 protein show significant overlapping expression in addition to a number of SOX family member-specific expression patterns. SOX6 expression in the endocardium, endocardial-derived cells, and coronary endothelium demonstrates that SOX6 could have an important role in valvuloseptal and coronary vessel development. xv This dissertation presents findings that Sox6 deletion from the endothelium/endocardium results in cardiovascular abnormalities including ventricular septal defects, enlarged atrioventricular valves, irregular coronary vasculature, and thin myocardium. Quantification experiments reveal that the loss of SOX6 from the endothelium/endocardium leads to an increase in the number of cells in the anterior leaflet of the mitral valve. This project identifies SOX6 as a novel player in heart development. It opens doors for research into the specific mechanisms through which SOX6 is involved in regulating valvuloseptal and coronary vessel development.

Rights

Copyright is held by the author. All rights reserved.

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