Research
Cilia in the development of Left-Right Asymmetry
The development of non-random asymmetry along the left-right axis is a unique feature of vertebrate development. Defects in this process in mouse and man commonly affect the development of the heart and result in severe congenital cardiac anomalies. Our goal is to understand the mechanism by which embryonic cilia create and signal left-right positional information, and to investigate whether cilia have essential roles in other developmental processes.
Cilia in Heart Development
Our work on cilia at the LRO, and previous work on cilia in the kidney and endothelial cells, demonstrates that cilia can be mechanosensors. We have identified cilia in a dynamic distribution in the developing heart, suggesting that intracardiac cilia are cardiac mechanosensors that integrate contraction and flow with morphogenesis. Our goal is to understand intracardiac cilia as mechanosensors during heart development, especially in the formation of heart valves.
Genomics in Congenital Heart Disease
How does understanding the novel and remarkable mechanism by which cilia drive left-right and cardiac development connect to patients with congenital heart disease? To this end, we have established collaboration with Richard Lifton and the Yale Center for Genome Analysis, and have become part of the Pediatric Cardiac Genomics Consortium (PCGC). The PCGC has recruited ~14,000 patients with CHD so far and aims to apply current genomic approaches in order to develop a more global understanding of the genetics of congenital heart disease. Work is ongoing to begin to connect genotype with clinical outcome and reconnect the developmental biology work with clinical pediatric cardiology.
Epigenetics in Cilia and Cardiac Development
Our whole exome sequencing of CHD patients and their parents has allowed us to identify a multitude of de-novo dominant mutations in chromatin remodeling genes. Interestingly, upon creating knockdown animal models for a few of these CHD-associated chromatin remodeling genes, we found that they had ciliary motility defects in addition to cardiac defects. Our current work is to understand how these chromatin remodeling genes, currently focusing on the H2Bub1 mark catalyzed by the RNF20-complex, mechanistically lead to ciliary and cardiac abnormalities during development.
Picture Credit: Lightsheet reconstruction of an E9.5 mouse heart with CD31 (endocardial marker) in white. Picture by Kathryn Berg.