Research

Hematopoiesis

Most of our studies are aimed at understanding how mesodermal derivatives commit to the hematopoietic fates during development. In the vertebrate embryo, hematopoietic cells are specified through four independent waves of precursor production. The first two are termed primitive, in that embryo-specific cell types are born, and include transient waves of erythrocytes and macrophages. The latter two waves produce definitive precursors, defined by their potential to generate multiple lineages of adult hematopoietic cells. Definitive hematopoiesis initiates with the formation of erythromyeloid progenitors (EMPs) in the posterior blood island.  While EMPs exist only transiently, they appear to give rise to adult tissue resident macrophages in both the mouse and the zebrafish.  Last to appear but most potent are hematopoietic stem cells (HSCs), which maintain homeostasis of the adult blood-forming system. Through confocal timelapse imaging and lineage tracing analyses, we have recently demonstrated that HSCs derive directly from ventral, aortic endothelium during development.  Importantly, HSCs appear to similarly derive from this hemogenic endothelium across vertebrate phyla, suggesting that lessons learned in one system will inform others.  In this manner, we are working to develop our findings from the zebrafish embryo into improved methodologies to instruct HSC fate in vitro from human pluripotent precursors, a feat that is not currently possible.

Immunity

We are also interested in understanding the ontogeny of immunity in the zebrafish embryo. Fertilization occurs externally in zebrafish, and the resulting embryos are autonomous from the beginning. Early embryos placed into solutions containing high bacterial titres are extremely resistant to infection. We are examining the components of this early immunity, with the goals of identifying the effectors of innate immunity and developing models of bacterial, protozoan, and helminth infection. We have identified dendritic cells in the zebrafish, and are working to determine when and where antigen presentation occurs to prime the adaptive immune response.  We have also discovered that microglia, the resident phagocytes of the brain, are seeded by two different waves of developmental precursors.  How these seeding events occur, and how each population may differ in function remain active topics in the laboratory.