Cilia and Flagella

Abstract Eukaryotic cilia and flagella are hair‐like cellular appendages composed of specialised microtubules and covered by a specialised extension of the cellular membrane. Their structure, genes, proteins and functions are highly conserved throughout evolution from protists to humans. Ciliary defects lead to physiological dysfunctions, developmental disorders and disease. Cilia and flagella have three, often interrelated functions: (1) As motile organelles beating like whips or oars, they propel cells through their environment or transport fluids along the surfaces of ciliated epithelia. (2) Both motile and nonmotile cilia act as antennae, sensing environmental cues and metabolic compounds and initiating specific cellular responses. (3) Their microtubules act as railroad tracks, along which molecular motors transport other molecules out to the ciliary tip and back to the cell body – a process called intraflagellar transport. Given these functions, cilia and flagella are micromachines and they act as cybernetic devices to receive, process and communicate information. Key Concepts Structural concepts in ciliary/flagellar axoneme assembly and function include the template function of the basal body, the polarity of the microtubules and the enantiomorphic asymmetry (handedness) of the axoneme. The assembly of the axoneme is tightly regulated by the expression of specific genes, by the limited amount of axonemal precursor proteins and by kinase enzymes. The mechanochemical force for motility is provided by dynein arms (large multisubunit ATPase enzymes) that cause the doublet microtubules to slide past each other. The beating of cilia and flagella depends on many biochemical factors including the different effects of outer versus inner dynein arm motors, the DRC (dynein regulatory complex) and DRC–radial spoke interactions mediated by kinases. The waveform of beating cilia/flagella also depends on the precise geometric assemblage of the axoneme structures, the mechanical properties of those structures and principles of the Geometric Clutch hypothesis. Associated with ciliary/flagellar membranes are numerous ion channels and signalling molecules. Intraflagellar transport (IFT) involves anterograde and retrograde transport of specific molecules along the axoneme (via kinesin and dynein motors respectively), and it is an essential process for ciliary/flagellar assembly and their signalling functions. The ciliary gate is formed by the membrane collar at the base of the cilium and by the stellate fibres of the basal body; it functions to sort, modify and permit entry of only membrane and protein constituents destined for transport and incorporation into the developing cilium. Mutations in genes encoding structural and functional proteins of cilia and flagella lead to innumerable diseases and disorders called ciliopathies. Eukaryotic cilia and flagella are estimated to have evolved roughly a billion years ago, following the appearance of the genes for tubulin (from bacteria) and proteins that establish the ninefold symmetry.