Academic Background

Ph.D., 1991, University of Minnesota

Function of the Mammalian Primary Cilium and Mechanisms of Eukaryotic Ciliary Assembly

We are interested in the function of primary cilia.  These organelles play vital roles in the development of mammals and in the etiology of diseases such as polycystic kidney disease and blindness.  Our work combines in vitro cell culture studies with mutant mouse models to understand the role of cilia in controlling kidney architecture and the formation of the photoreceptor outer segment.

In the kidney, the epithelial cells lining the ducts and tubules of the nephron have prominent primary cilia extending from their surface into the lumen of the duct.  We showed that the Tg737 mouse model of polycystic kidney disease has defects in these cilia.  The gene mutated in the Tg737 mouse encodes the IFT88 subunit of the intraflagellar transport (IFT) particle. IFT is bidirectional movement along the length of cilia that is thought to carry materials needed for assembly and maintenance of cilia and flagella.

       Figure 1.               

It is thought that primary cilia on kidney epithelial and other cells are sensory organelles that monitor the extracellular environment.  Information perceived by cilia control aspects of cell physiology including proliferation and differentiation, along with cellular and organ architecture.  We are currently focused on understanding how cilia function to maintain the normal architecture of the kidney and prevent cystic disease.  To do this we have created a floxed allele of the gene encoding the IFT20 subunit of the IFT particle.  Deletion of this gene in the kidney causes severe polycystic kidney disease.  During the development of cystic disease in this animal, the collection ducts (labeled green in Figure 2) greatly enlarge and disrupt the architecture of the kidney.   

        Figure 2.            

Another focus of the laboratory is to understand how the outer segments of vertebrate photoreceptor rod and cone cells are assembled.  These structures are highly modified cilia and require intraflagellar transport for assembly.  Defects in transport cause progressive retinal degeneration eventually leading to blindness.  To study the role of intraflagellar transport in photoreceptor outer segment assembly, we deleted IFT20 specifically in cone cells.  This initially causes photopigments to accumulate in the cell body and causes cone cell degeneration, eventually destroying all the cones.  Rod cells are not affected in these animals.  In Figure 3 cone outer segments are labeled green, rod outer segments are labeled red, and photoreceptor nuclei are labeled blue.  

Figure 3.