Electronic Thesis and Dissertation Repository


Doctor of Philosophy


Physiology and Pharmacology


Qingping Feng


Congenital heart defects (CHDs) are the most common human birth defect and the leading cause of death from a birth defect in the first year of life. Thus, a further understanding of the mechanisms underlying CHDs, which could lead to improved diagnosis and treatment, is crucial. The small GTPase, Rac1, acts as a pleiotropic effector of numerous cellular processes; however, little is known about its role in embryonic heart development. The aim of this thesis was to investigate the role of Rac1 signaling in cardiac development. Using the Cre/loxP system, mouse models with an anterior second heart field (SHF) or ventricular myocardium specific deletion of Rac1 were generated. I demonstrated that mice with a SHF Rac1 deficiency displayed a spectrum of CHDs including bifid cardiac apex and septal defects. These Rac1 deficient cardiomyocytes failed to undergo polarization. In addition, migration and lamellipodia formation was disrupted in Rac1 deficient cardiomyocytes. Decreased SHF Rac1 signaling led to increased apoptosis and downregulation of several cardiac developmental transcription factors. Furthermore, my data showed that organization of anterior SHF progenitors was disrupted, leading to a spectrum of outflow tract (OFT) defects in Rac1 deficient mice. Cardiomyocytes with a Rac1 deficiency failed to polarize and undergo myocardialization, causing misalignment of the OFT. At P0, Rac1 deficient aortic valves displayed defects in maturation and remodeling and intrauterine echocardiography performed at E18.5 showed severe aortic valve regurgitation. Finally, I showed that a Rac1 deficiency in the ventricular myocardium resulted in ventricular noncompaction and defective trabecular development. The myocardium proliferation rate was significantly decreased and expression of the planar cell polarity protein, Scrib, was reduced. Actin polymerization was severely disrupted and cardiomyocytes failed to polarize in E18.5 Rac1 deficient ventricular myocardium. In conclusion, my thesis is the first to show that Rac1 signaling regulates several pathways, including proliferation, cell survival, gene expression and actin polymerization during embryonic heart development. Through these mechanisms, Rac1 is a critical regulator of cardiomyocyte polarity, septal and OFT development and formation of the ventricular myocardium.

293D E15.5 Racff - movie.mpg (13000 kB)
3D Reconstruction Rac1f/f OFT

293F E15.5 Rac1SHF -movie.mpg (11607 kB)
3D Reconstruction Rac1SHF OFT