Our research group is interested in the developmental signals that control growth and differentiation during vertebrate kidney organogenesis. Because the nephron is the functional unit of the kidney and the pathophysiological site of human kidney diseases, including those affecting the glomerulus, we have concentrated our research efforts on understanding the molecular/genetic regulation of nephron formation. Topics of investigation include nephron segmentation, tubulogenesis, and glomerular morphogenesis.

Our lab is using the zebrafish embryonic kidney or pronephros as a model sytem for investigating kidney organogenesis due to its several experimental advantages. The pronephros, made of two unit nephrons with glomerulus, tubule, and duct segments, shares structural features with nephrons from higher vertebrates yet is anatomically much simpler. Zebrafish pronephric development follows developmental stages common to nephrogenesis in mammals but is complete by 48 hours post fertilization (hpf), much faster than in mouse. Embryonic development occurs ex utero offering the potential for experimental manipulation such as cell labeling and cell transplantation. In addition, zebrafish embryos are transparent allowing the direct visualization of pronephric organogenesis in the living embryo and in transgenic GFP expressing reporter strains. Finally, renal physiological function can be assayed by the uptake of injected, fluorescently labeled small molecules such as dextran.

The zebrafish mutant no isthmus (noi) contains a mutation in the transcription factor Pax2.1 and is associated with pleiotrophic defects in midbrain/hindbrain patterning, retinal axon pathfinding, and pronephric development. During pronephric organogenesis, pronephric tubules do not form in noi mutants (Development, 127, pp. 2089-98, 2000). The developmental basis lies in the expansion of glomerular specific gene expression domains within kidney tubule progenitor cells suggesting that the Pax2.1 transcription factor is important in controlling nephron patterning events. We are using the noi Pax2.1 mutant as an entrance point into investigating the genetic pathways regulating nephron segmentation and tubular differentiation. Approaches involve genetic screens, antisense morpholino technology, microarrays, and transgenesis.

In collaboration with Karl Tryggvason’s group in the Division of Matrix Biology, we are also using the zebrafish to study the function of several glomerular associated genes. These include genes expressed uniquely in the glomerular podocytes, mesangial cells, and capillary endothelial cells. Our goal is to identify central regulators of glomerular morphogenesis and physiological function.