Notochord development and associated IVD disease

We recently identified three Brachyury-bound, notochord-specific shadow enhancers that are conserved among vertebrates and could pose as important fate-sensors for nucleus pulposus-like cells, notochord organoids, and IVD tissue. We are currently testing the upstream input at these enhancers controlling Brachyury expression in the notochord and how they influence notochord and intervertebral disc development. Further, knockout studies of those enhancers in mice revealed developmental tissue-specific phenotypes affecting the notochord and neural tube closure. Together with an international pool of collaborators, I extend my work into other models towards establishing the mechanistic and clinical relevance of our findings. Overall, my work has generated novel insights and tools towards a better understanding of notochord development.

In vivo genome editing, transgenesis methods and more

Over the past decade, I have developed methods for disease modeling in zebrafish using genome editing and transgenic approaches. I was fortunate to be one of the first users of zinc finger nucleases to generate mutant alleles in zebrafish, expertise that I translated into a full research program using CRISPR-Cas9-mediated genome editing for disease modeling. I further use transgenic approaches to define cis-regulatory elements of tissue-specific genes to identify their involvement in vertebrate development as well as congenital diseases. Together with my collaborators, I have recently published an updated toolkit and guidelines to efficiently generate transgenic zebrafish using Tol2-based random integration of transgenes which was highly appreciated by the community. Based on these successes, we are leveling zebrafish transgenesis up by establishing safe harbor loci in the zebrafish genome that can be used for single, site-directed insertion of transgenes using phiC31. More recently, I invested in standard development and advancing a zebrafish toxicology phenotype atlas. Overall, my work has generated approaches widely applied in the community for mutant and transgene generation in zebrafish and beyond.

Genetic and mechanistic causes of congenital diseases affecting mesodermal organ systems

We further pursue the developmental defects causing Thrombocytopenia-Absent-Radius (TAR) syndrome in the spectrum of hematopoietic and heart-hand malformations and continue pilot efforts to define congenital heart disease (CHD)-causing mutations from patient data in the zebrafish proxy.

Cell fate mechanisms of the lateral plate mesoderm and associated diseases

We recently identified several mesodermal enhancer elements that are conserved among vertebrates. This work harnesses our latest advances in enhancer discovery and the required transgenic tools to perform thorough testing in zebrafish and beyond. Our newly discovered mesothelial, notochord and hematopoietic enhancers could pose as important fate sensors for in vitro differentiation and as cross-species readouts.