From Gene to Phenotype: Deciphering Cardiac Development and Disease

Dissertation by Kathryn Byerly

The heart's development and its malfunction in disease share many underlying biological processes, but we don't fully understand how. This gap makes it difficult to develop new treatments. This dissertation uses mouse models to study two questions: how the heart forms normally, and how it gets damaged during disease.

The main focus to understand development is a protein called DCHS1, which helps cells "know" their position in an organ and communicate with neighbors. Using specially engineered mice, the researchers mapped exactly when and where DCHS1 is active during heart development. It turns out it's mainly present before birth in the cells lining blood vessels and in connective tissue cells, not in the heart muscle cells themselves. Interestingly, when DCHS1 was removed entirely, heart muscle cells divided abnormally, even though DCHS1 wasn't inside those cells.

This means DCHS1 controls heart muscle growth indirectly, through neighboring cells. Essentially, the DCHS1 in other cells (non-heart muscle cells) are communicating with the heart muscle cells to stop heart muscle growth.

The researchers also discovered that DCHS1 gets physically cleaved, or cut in two, during development, separating its inner and outer portions. To figure out why, researchers created mice missing just an inner portion of DCHS1, called the intracellular domain. These mice showed the same heart problems as the full knockout (the mouse without DCHS1 entirely), confirming that this inner piece is critical for normal heart development. These mice also had facial, skeletal, and brain abnormalities resembling a rare human condition called Van Maldergem syndrome, suggesting DCHS1's inner domain plays a broader role than previously recognized in other organ systems outside of the heart.

The second part of the work tackles rheumatic heart disease (RHD), heart valve damage caused by strep throat infections that go untreated and lead to acute rheumatic fever. RHD remains a major cause of heart disease worldwide.

By working with some of the world leading experts in RHD through a trans-Atlantic Leducq network, the McCormick and Norris laboratories developed the first mouse model that reproduces human RHD, including the valve damage, inflammation, and scarring seen in patients. This opens the door to studying how the disease progresses identifying biomarkers for disease severity, and testing potential treatments. Together, this work spans across multiple organ systems, and builds new tools for understanding both how the heart develops and how it can be damaged.

Discussion:

DCHS1 has proved to be far more interesting than previously appreciated, because it functions as a dynamic communication hub: sensing the physical environment around a cell, getting snipped into pieces in a carefully timed way during development, and sending signals from inside the cell that shape how the heart grows.

One of the most striking findings is that DCHS1 controls heart muscle cell growth indirectly: it's expressed in supporting cells (fibroblasts and endothelial cells), yet when it's missing, the muscle cells themselves proliferate abnormally. This challenges the long-held assumption that heart muscle growth is controlled mainly from within the muscle cells themselves.

The inner portion of DCHS1 (its intracellular domain) proved to be a critical piece. Removing just this domain was enough to reproduce heart, skull, skeleton, and brain abnormalities seen in DCHS1-knockout mice and in humans with Van Maldergem syndrome, a rare developmental disorder. This suggests that many features of this syndrome, previously attributed to faulty cell-to-cell contact on the cell surface, actually depend on signaling occurring inside the cell.

The rheumatic heart disease work, while arising from a completely different cause (immune damage from strep infections), connects to the same underlying theme: the same fundamental processes that build the heart during development are reactivated when the heart is injured.

The first mouse model of this disease revealed that while heart valve scarring may still be reversible early in disease, the heart muscle itself sustains irreversible damage much sooner than previously recognized, suggesting patients may need earlier and broader treatment.

Taken together, these studies reinforce a unifying idea: whether heart disease is congenital or acquired, it ultimately reflects a breakdown in the cellular communication and tissue organization processes that the heart depends on throughout life.