Iain A. Drummond, Ph.D.
Associate Biologist, Renal Unit, Massachusetts General Hospital
We study kidney organogenesis using the zebrafish to explore conserved molecular mechanisms underlying kidney cell specification, differentiation, and organ patterning. We also study organ pathologies that results from mutations in genes required for cilia biogenesis and function. These include kidney cystic disease, retinal degeneration and left-right asymmetry defects.
Kidney progenitor cells. During gastrulation, expression of the odd skipped related1 finger transcription factor defined a broad band of intermediate mesoderm that will later give rise to the kidney and vasculature. We have found that knockdown of osr1 expression results in failure of proximal tubule epithelial differentiation, increased angioblast and failed glomerular morphogenesis. We are pursuing the hypothesis that osr1 functions during gastrulation to define ventral mesoderm organ fields and control the cell fate choice between kidney and vascular cell differentiation. We are also defining a novel role for osr1 in podocyte differentiation.
Cilia and organogenesis. Kidney cystic disease, retinal degeneration and left-right asymmetry defects can all be linked to defects in apical cilia. We are characterizing and positionally cloning zebrafish cystic kidney mutants to further understand the roles of cilia in development and disease. We find that the double bubble mutant gene encodes IFT172, a gene required for cilia formation. The fleer mutant encodes a novel TPR repeat protein that regulates tubulin polyglutamylation and ciliogenesis. We are also demonstrating novel roles for IFT genes in cilia-independent processes such as intracellular vesicle transport. Our goal is to characterize additional ciliogenic genes and define their function in epithelial cell differentiation.
Modeling Human disease in zebra fish. Modeling human diseases in the zebrafish creates opportunities to better understand disease mechanisms and screen for treatments. Human polycystic kidney disease (PKD) is one of the most common genetic diseases. We fnd that zebrafish homologs of PKD genes are also essential for proper pronephric kidney development. Homologs of other disease genes like Nephrin and Podocin are required for glomerular function, the filtration of blood. Defects in these genes result in proteinuria or nephrotic syndrome. Using assays we developed, we described a novel function for the crumbs-interacting, apical pathway protein mosaic eyes (moe) in podocytes: loss of moe function results in massive proteinuria and disrupted cell architecture. We also have recently found that phospholipase C epsilon is required for zebrafish glomerulus formation and function, implicating calcium and DAG signaling in this process. Further studies are aimed at understanding the role of these signaling pathways in podocyte cell biology.