The primary cilium, a slim microtubule-based organelle that projects from the surface of vertebrate cells, has been the focus of intensive studies transforming it from a poorly understood curiosity into a structure recognized for its importance in development, inherited human disease and cancer. Cilia and flagella are ancient structures present in organisms as diverse as single celled eukaryotes and humans. The evolutionarily conserved mechanism of Intraflagellar Transport (IFT), first described in the alga Chlamydomonas
, is essential for the construction and maintenance of these structures in all species1, 2
In the past decade, the function of mammalian primary cilia has been revealed by both developmental genetic analyses and human genetic studies. Disruptions of the primary cilium have been associated with the common disorder human cystic kidney disease3–6
. In addition, rare recessive human disorders known as ciliopathies, with complex syndromes that include cystic kidneys, obesity, mental retardation, blindness and various developmental malformations, have been shown to be caused by mutations in proteins localized to cilia and ciliary basal bodies (reviewed in7–10
). In parallel, genetic studies in the mouse demonstrated that cilia are essential for signaling through the Hh pathway, a crucial signaling pathway for organizing the body plan, organogenesis and tumorigenesis11
The importance of primary cilia in vertebrate development was first revealed in genetic experiments that demonstrated that cilia are required for survival and patterning of the mouse embryo11
. Phenotypic, genetic and biochemical analysis then showed that embryonic phenotypes of the cilia mutants were caused by disruption of Hh signal transduction. This unexpected finding raised many questions, including why the cilium is a good locale for signal transduction, why cilia are required for vertebrate but not invertebrate Hh signaling, and whether primary cilia are important in regulating other developmental signaling pathways.
Other recent experiments have suggested that additional developmental signaling pathways help regulate the formation of cilia. The most complete studies have implicated components of the planar cell polarity (PCP) pathway in the regulation of the position and formation of cilia. These processes, which could indirectly regulate the activity of Hh signaling, appear to be particularly important during organogenesis.
Here we review the relationships between primary cilia and signaling pathways during vertebrate embryonic development. After describing the evolutionarily conserved mechanism of IFT, we review the evidence that Hh signaling requires IFT and cilia. We then describe recent work suggesting that the primary cilium in vertebrate embryos is specialized such that Hh signaling is restricted to the cilium. After considering whether additional developmental signaling pathways require cilia, we discuss the evidence that other signaling pathways regulate ciliogenesis. We conclude with a discussion of how the findings on the relationship between cilia and developmental signals are beginning to explain the syndromes seen in cilia-related human diseases, focusing on the formation of kidney cysts, a hallmark of disorders caused by abnormal primary cilia.