Why are capillaries narrower than an aorta? What regulates the diameter of the various segments of the long nephrons in our kidneys? My research studies the mechanisms used by epithelial cells to measure and regulate the diameter of small tubules. We use the tiny roundworm Caenorhabditis elegans to look at a series of genes whose function is required to prevent its tubules from swelling into fluid-filled cysts. This roundworm grows quickly on a bacterial lawn on Petri plates, and is clear, so we can watch the development and growth of its renal tubules (called the excretory canals) in living creatures.
We are cloning a series of 12 genes named exc that normally maintain the hollow excretory canals as narrow tubules. Most of the genes have now been cloned, and they encode proteins that surround the hollow (apical) surface of the canals, through which liquid flows. The genes encode proteins such as the cytoskeletal protein spectrin, an activator of the actin-regulatory protein CDC42, a secreted mucin, an ion channel, a molecule involved in mRNA processing, and most recently, a protein also found in large quantities in the human gut that may regulate the immune system there. Intriguingly, when some of the proteins are mutated, the result is tubules that defects at the apical surface that causes large fluid-filled cysts; but when the proteins are present in very high amounts (i.e. too much of a good thing), the tubules have defects at the outside (basal) surface that cause them to be too short. We are now using genetics and immuno-electron microscopy to determine how these components work together to regulate simultaneously the function and structure of the hollow excretory canals.
As a related project, we are looking at human proteins that regulate the structure of tubules in our bodies-especially in the kidneys, liver, and vasculature. Defects in the PKD2 gene, a calcium ion channel, results in autosomal dominant polycystic kidney disease (PKD), the most common lethal genetic disease. Surprisingly, in nematodes, this same protein regulates the function of the nervous system! We are studying this protein in C. elegans in order to understand better what nematode behavior can tell us about kidney disease, and how calcium levels in our kidney maintain the normal structure and function of our renal tubules.
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