Date of Award

2007

Degree Type

Thesis

Degree Name

Master of Science

Program

Physiology

Supervisor

Thomas A Drysdale

Second Advisor

Frank Beier

Third Advisor

Kevin J. Leco

Abstract

Retinoic acid (RA) plays a crucial role in regulating cardiomyocyte differentiation and heart tube formation, but excess RA inhibits cardiomyocyte differentiation. We have used microarray technology and whole mount in situ hybridization to investigate the mechanism by which RA might alter cardiogenesis. Our results showed that RA inhibits cardiomyocyte differentiation at least partially through increasing follistatin gene expression and decreasing BMP signaling. Using cultured explants of the heart region, we demonstrated that addition of BMP4 and activin rescued the inhibitory effects of follistatin and RA on cardiomyocyte differentiation. These results indicate that the increased follistatin (FS) gene expression, known to decrease BMP signaling, may be responsible for the inhibition of heart development. In order to investigate the role of follistatin in cardiogenesis, we also examined follistatin’s developmental profile. We found that follistatin is expressed in the heartforming region in early heart development, which suggests that follistatin is involved in cardiogenesis. In addition, we first showed that excess RA inhibits Tbx20 gene expression in the heart-forming region. This provides another mechanism by which excess RA inhibits cardiogenesis in addition to the known inhibition of Nkx2.5 expression and BMP signaling.

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