http://www.loc.gov/mods/v3 http://www.loc.gov/standards/mods/v3/mods-3-2.xsd
role of serum response factor (SRF) in the formation of cardiac neural crest (CNC)-derived branchial arch arteries and outflow tract cushion
xiii, 111 leaves : illustrations ; 28 cm.
ABSTRACT: Rationale : Cardiac neural crest cells (CNCCs) are multipotent migratory cells that contribute to the formation of the cardiac out flow tract and branchial arch arteries. Defective cardiac NCCs account for varies of congenital heart disorders (CHD). The overlapping expression pattern of SRF gene and CNCCs expression tool Wnt1-Cre suggested that SRF may function in this region. Also in vitro SRF can affect smooth muscle cells that also can be derived from CNCCs. Recently miRNAs, many SRF regulated, have become a major focus of the research in cancer and developmental biology including heart. They emerged as important factor in a post transcriptional regulation network. Objective : To study the roles of SRF affected miRNAs in cardiac NCCs cell differentiation and migration, we used Wnt1-Cre to conditionally knockout Dicer gene that plays an important role in the final step for processing mature miRNAs and used this Cre to knockout SRF gene that plays an important role in a number of miRNAs transcription. Methods and Results : All of Dicer / Wnt1-Cre knockout mutant embryos displayed multiple organ defects, especially including cardiovascular anomalies, including aortic arch patterning defects, aorticopulmonary artery defects and ventricle septal defects, which resemble to human CHD. Interestingly, cardiovascular defects in Dicer / Wnt1-Cre mutant are highly similar to those defects in SRF mutant embryos (Srf / Wnt1-Cre). Both Dicer / Wnt1-Cre and Srf / Wnt1-Cre mutant embryos showed enlargement of arch artery 3rd and regressing or repressing narrowed arch arteries 4th and 6th. Both mutants showed shortened outflow tract (OFT), and failed to demonstrate progession of cardiac NCCs into proximal OFT. Also, we found that both mutant embryos have reduced miR-125b, miR-145, miR-181, miR-483 and miR-690, which contain several SRF-binding motifs : CArG box in their promoter or enhancer regions. These microRNAs were also downregulated in Srf-/- ES cells and can be restored by human SRF expression in Srf-/- ES cells. Conclusion : Our studies demonstrate a central role of matured miRNAs regulated by SRF in migration and differentiation of cardiac NCCs, while microRNAs regulate precise protein level of transcription factors to execute the processes of cardiovascular and heart formation.
"Submitted to the Office of Research and Graduate Studies The Texas A&M University System at Health Science Center in partial fulfillment of the requirements for the degree of Doctor of Philosophy August 2010."
Approved as to style and content by: Robert Schwartz, Dekai Zhang, James Martin, Magnus Höök, Brad Amendt.
Keyword : miRNAs, congenital heart disease, neural crest cells, outflow tract, Dicer, SRF, cardiovascular development
Ph. D. Texas A&M University System Health Science Center 2010.
Includes bibliographical references (leaves 85-104).