What we do:

All animals start life as a single cell, the fertilized egg, which divides into hundreds of different cell types. Our long-term research goal is to understand the genes, molecules and developmental mechanisms that regulate the assignment of different cell identities in functionally appropriate positions in the developing vertebrate embryo, and to utilize this knowledge for the advancement of human medicine. This top-down approach utilizes embryonic phenotypes to uncover novel genetic pathways and cellular mechanisms ranging from extracellular signaling to genome-wide regulation of transcriptional networks.

Left-Right Axis Formation and Cilia

Our lab is a founder and leader in the field of vertebrate left-right development. Our research utilizes zebrafish, Xenopus and mice to discover the genes, molecular and cellular mechanisms that control asymmetric development of the brain, heart and gut. We have discovered novel mechanisms by which major cell-cell signaling pathways (FGF, TGFbeta and Wnt) control cilia function, cell migration and downstream pathways.

Cardiac Development

We are using genome-wide approaches to elucidate the Gene Regulatory Networks that control heart development in zebrafish, with the goal of understanding human complex congenital cardiac defects that are the leading cause of death in children in the first year. As one of four NHLBI-funded Cardiovascular Development Centers in the country, we have built a team developmental biologists, cardiac physiologists, and experts in chromatin structure, genome-wide gene network profiling, bioengineering and bioinformatics. We have created approaches that exclusively mark either polysomes or whole nuclei in a lineage-specific manor, allowing us to perform genome-wide expression profiling and analysis of the epigenome (RNA-Seq, ChIP-Seq, DNA bisulfite sequencing, etc) from rare cell lineages in the context of a whole animal at any stage of development. In parallel with our zebrafish cardiovascular projects, we have a collaborative project developing human amniocytes, which have nascent stem cell characteristics, into cardiomyocyte lineages with the long-term goal of clinical repair of human congenital heart defects.

Genomics in zebrafish

Driven by our interest in Gene Regulatory Networks in development and disease, and zebrafish's reputation for a challenging genome, we have created several molecular and bioinformatics approaches to discovering the molecular lesions of new mutations and rapidly identifying extant mutations. This will allow us to more fully manipulate the zebrafish genome in order to generate models systems of human genetic disorder, including specific cancers and complex heart disease.

The Glycocode Hypothesis

Heparan Sulfate Proteoglycans (HSPGs) are cell surface proteins with long chains of repeating sugar units (glycosaminoglycans; GAGs). Our discovery that a family of HSPGs control cell signaling pathways, cell migration and fibrillogenesis led to our focus on large gene families that regulate proteoglycan biochemistry and function. Our results suggest the existence of a "Glycocode" in which specific sulfation patterns on cell surface GAGs control specific cell-cell signaling decisions, including the modulation of Wnt, BMP and FGF signaling pathways. The Glycocode could provide enormous molecular diversity that dwarfs the informational content of the genome. Discovering out how this Glycocode is regulated and how it is utilized in biology will be one of the major challenges in the "postgenomic era" and will provide important therapeutic targets for a wide range of human diseases.