This is the first molecular demonstration of how primary cilium, a specialized cellular organelle found in most cell types in the body and which have been neglected for decades, mediates a physiological function—sensing fluid flow. Furthermore, our finding gets to the molecular mechanisms underlying one of the most common genetic diseases.

It describes a new discovery using a specialized methodology that can be used in other systems.

Primary cilium is a thin, hair-like structure extending from the apical membrane of a cell. It has nine sets of microtubules arranged in a ring. The primary cilium in the kidney has been observed by electron-microscopists for many years but without known function. They have been thought to be evolutionary vestiges for a long time. We found that polycystin-1 and -2, proteins mutated in a common genetic disease—autosomal dominant polycystic kidney disease—are localized to the primary cilia in the kidney. Kidney cells which we isolated from normal mice but not mice with polycystin-1 mutations respond to physiological fluid flow with a calcium signal, suggesting that polycystin-1 (which is a receptor-looking molecule) mediates mechanosensation in the primary cilia of kidney epithelial cells. We next tested whether the calcium ions come into the cell through the polycystin-2 channel (which we and others previously worked out) by blocking the channel with an antibody specific to polycystin-2. We found that, indeed, the calcium signal was blocked. Thus we have shown that polycystins are key molecules involved in mechanosensation in kidney cells. We describe a model in which polycystin-1 and -2 form a mechanoreceptor-channel complex and transduce a mechanical signal into a calcium signal, which is a well-known second messenger in cellular signaling. We further explored how the initial signals are amplified in the cell. Thus, we have provided molecular insights into an important physiological process mediated by an organelle that has been neglected for decades. We have linked this finding with a common genetic disease. Our finding can be extended to our molecular understanding of other cystic diseases. Indeed, we now know that a number of cystic diseases that mostly affect children (e.g. autosomal recessive polycystic kidney disease) are caused by mutations in proteins that are localized to cilia. The significance of our finding has gone beyond kidney disease—the determination of the asymmetry of our body plan also uses a similar flow-sensing mechanism during embryonic development. I will not be surprised if there is an exposure of discoveries describing the role of primary cilia in a variety of cell types over the course of the next several years.

My laboratory has been working on polycystic kidney disease for nearly a decade. It was a natural extension of our studies on the molecular mechanisms underlying the disease. The studies in lower model organisms (Chlamydomonus and C. elegans) have facilitated this discovery.