In the prevailing model, the movement of Shh signaling components into the cilium, up and down the axoneme by IFT, and CHIR99021 out of the cilium again, sequences and paces the steps of Shh signal

transduction (Goetz and Anderson, 2010). In the face of a growing bias toward “translational research,” it is a healthy lesson that studies of a unicellular alga led to profound insights into a class of human disease syndromes. These syndromes show a bewildering variety of abnormalities, such as cystic disease in the kidney, polydactyly, brain malformations, hydrocephalus, blindness, anosmia, obesity, and cognitive deficits. How could single diseases involve pathology in so many different systems? The answer appears to be that affected organs contain ciliated

cells, and that genetic mutations associated with the syndromes disrupt ciliary proteins, frequently those of the basal body, but also IFT, dynein motor, and other proteins (Christensen et al., 2008, Fliegauf et al., 2007, Goetz and Anderson, 2010, Lancaster and Gleeson, 2009, Sharma et al., 2008, Sloboda and Rosenbaum, 2007 and Veland et al., 2009). As expected, relevant genetic mutations affect both secondary and primary cilia. Many disorders, however, arise specifically from dysfunction of primary cilia. Neural cells implicated in some of the anomalies listed above include ORNs with immotile cilia, primary ciliated neural progenitor cells, choroid plexus cells, photoreceptors, and neurons of the mature brain. Key experimental links between

the primary cilium and human disease arose from research on polycystic kidney disease (PKD). GDC0449 Mutations in two human genes, PKD1 and PKD2, cause autosomal dominant PKD, and both genes were found to have homologs in C. elegans whose protein products localize to cilia ( Barr et al., 2001 and Barr and Sternberg, 1999). Further, the Oak Ridge Polycystic Kidney (ORPK) mouse, a model of PKD, is hypomorphic for Ift88, the mouse homolog of Chlamydomonas IFT88 (see Table 1) and has stunted primary cilia ( Pazour et al., 2000). In kidney epithelial cells primary cilia respond to fluid flow by passively bending, which initiates a calcium ion (Ca2+) influx, illustrating ciliary transduction of a sensory stimulus ( Praetorius and Spring, 2001). The stunted cilia of PAK6 the OPRK mouse cannot perform this function. Whether defective cilia mechanoreception is a central cause of cyst development in PKD is debated ( Davenport et al., 2007), but these findings nonetheless reveal the primary cilium as a sensory detector. Furthermore, the ORPK mouse remains an excellent model of human ciliopathic syndromes, developing a range of other abnormalities seen in human patients, ascribed to defective cilia ( Lehman et al., 2008). These observations launched a massive program of research on the genetics and cell biology of ciliopathic syndromes, reviewed extensively elsewhere (Badano et al.