New insights into how the heart forms may help identify heart defects

| Written by Guest Blogger
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This is a post by our guest writer Janelle Weaver, Ph.D.

The formation of the heart during development is a highly complex process that requires precise coordination between cells and molecular signaling pathways. The fruit fly has been widely used for studying the underlying cellular and molecular mechanisms, and a great deal is known about how the fate of heart cells is controlled by signaling pathways and transcription factors—proteins that control gene activity. But beyond that, events that regulate heart formation have not been clear.

A team of Sanford-Burnham researchers has discovered that a protein called Cdc42 plays an essential role in regulating heart formation during embryonic development in the fruit fly. As reported in the Journal of Cell Biologythe researchers found that interactions between Cdc42 and other proteins called tinman, zipper, and dDAAM control the shape of heart cells, thereby allowing heart tissue to wrap into a tubular structure that is essential for proper organ function.

“The complexity of human development and diseases such as congenital heart disease—defects in the structure of the heart—makes it necessary to model developmental processes in simpler model organisms, including the fly,” said senior study author Rolf Bodmer, Ph.D., director of the Development, Aging, and Regeneration Program at Sanford-Burnham. “We believe that our findings will pave the way for the identification of risk factors associated with congenital heart disease in humans.”

A change of heart

Cdc42 belongs to the Rho family of GTPases—enzymes that control important cellular processes such as cell shape and cell movement. Bodmer and his team previously showed that this protein interacts with a transcription factor called tinman/Nkx2-5 to enable the heart to contract and function normally in adult fruit flies and mice. In the new study, the researchers investigated Cdc42’s potential role in heart formation during embryonic development, hypothesizing that Cdc42 may regulate the organ’s structure by controlling the shape and movements of cells.

To test this idea, Bodmer and collaborators at Sanford-Burnham and the Hungarian Academy of Sciences examined fly embryo hearts with mutant Cdc42. They found that embryonic heart cells called cardioblasts were not properly aligned in one third of these hearts, leading to abnormalities in the shape of the organ. Remarkably, loss of Cdc42 function caused heart-muscle cells to form a layer instead of a tube. These findings suggest that Cdc42 is necessary to induce cell-shape changes and thereby direct the heart to form a tubular structure. By contrast, this protein did not affect the migration of cardioblasts, suggesting that heart formation is not influenced by Cdc42-induced changes in cell movement. “Our data point to a novel role for Cdc42 in heart development and change prior views of how the heart forms in the developing embryo,” said Georg Vogler, Ph.D., a postdoctoral associate in the Bodmer lab and lead author of the study.

Coordination is key

Because the heart defects occurred in only a fraction of mutant Cdc42 embryos, the researchers reasoned that other proteins could interact with Cdc42 to control heart formation. After examining various transcription factors in genetic experiments, they found that tinman strongly interacted with Cdc42 to control heart formation. Moreover, the number of defects in the shape of the heart was lower in embryos that were single mutant for Cdc42 compared with embryos harboring mutations that affected both Cdc42 and zipper, which belongs to a class of proteins involved in regulating cell shape and cell movement. The findings suggest that Cdc42 interacts with various proteins, including tinman and zipper, to control heart formation during embryonic development.

In addition to tinman and zipper, the researchers examined whether heart formation would be influenced by formins—proteins that are regulated by the Rho family of GTPases and play a key role in cell migration. Indeed, embryos with mutations affecting both Cdc42 and a formin called dDAAM showed severe heart defects not found in embryos with mutations affecting just one of these proteins, suggesting that Cdc42 also interacts with dDAAM to regulate heart formation.

Ultimately, the findings could have important implications for not only identifying risk factors associated with congenital heart disease, but also developing effective methods for organ transplantation. “Despite the advancements of stem-cell research, the aim to manufacture transplant organs still requires a better understanding of how organs are formed in vivo,” Bodmer said. “The fruit fly heart model, due to its simplicity, can therefore serve as a first blueprint of organ formation.”

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