In recent years, cilia — microscopic, tentacle-like extensions from biological cells — have risen from relative obscurity, and are now considered important to the understanding of many human afflictions.
Researchers describe recent discoveries involving cilia-related diseases (called “ciliopathies”) and highlight models that could be useful for systematic study of ciliopathies.
Helping move things around the body
Cilia perform a broad range of functions, including a starring role in cell signalling. Motile ones wiggle and so move fluids within the body — including cerebrospinal fluid in the brain. They’re also what’s in charge of moving eggs (ova) from the ovaries down the fallopian tubes to the uterus.
In humans, cilia are found on almost every cell in the body. Because of this, ciliopathies often make themselves known as syndromes with widely varying effects on a number of tissue types.
Cliia and epithelial cell layers
“Epithelial cell layers line all of the inner and outer body and organ surfaces in the human body, for example in the lung, intestine, pancreas and in the inner ear,” says Moritz Gegg of the Institute of Diabetes and Regeneration Research at the Helmholtz Center Munich in Germany, who was the lead author on a study published in October 2014.
Their work is based on the idea that cilia are precisely positioned on many epithelial cells. “Only through this exact positioning can cilia movements be coordinated so precisely that for example mucus can be transported from the lung or sound can be perceived from sensory inner ear hair cells,” says Helmholtz’ Heiko Lickert, one of the co-authors.
Cilia are anchored by the basal bodies to the plasma membrane, and, like many other organelles, must be localized to a specific position in a cell.
To ensure this, the body’s Planar cell polarity (PCP) machinery goes into action. It orients organelles in single cells, but also determines the position of these cells within the plane of an epithelial layer. A complete loss of this cell polarity machinery can lead to very severe developmental disorders — such as chronic bronchitis, deafness or other birth defects.
Several proteins assist in the formation of this cell polarity machinery by influencing the orientation of the intracellular cytoskeleton. Thus, a complex of PCP proteins can coordinate the localization of individual organelles and cells in the epithelial cell assembly. Although many proteins that regulate these processes are already known, scientists have wondered for a long time how both systems interact with each other to acquire planar cell polarity.
Gegg and other researchers created a model and found that two different proteins positios the basal body — and, thus, the cilia. Models without a particular functional protein (the uncharacterized gene Flattop, or Fltp) showed a defect in cilia formation on the surface of the lung epithelium — and the cilia in the inner ear were not correctly localized.
“A dysregulation of cilia formation and function leads to a wide spectrum of diseases in human, i.e. ciliopathies such as diabetes, chronic lung diseases, deafness and also cancer,” says Lickert.
Fltp could also be dysfunctional in patients with lung diseases. Loss of this protein leads to defects of the sensory cells in the inner ear.
In addition, there are indications that Fltp regulates cell division in the intestine. Says Gegg, “Further studies are needed to elucidate exactly how the protein complex consisting of Fltp, Dlg3, the core PCP proteins and the basal body proteins interacts with the cytoskeleton. In addition, the important question needs to be clarified to what extent this protein complex also fulfills a similar function in other epithelial cell types.”
More research on faulty cilia
In a December 2014 BioScience article, George B Witman, of the University of Massachusetts Medical School, and Jason M Brown, of Salem State University, also point to a number of human diseases in which cilia may play a role — for example, some cancers and neurological diseases may be related to ciliopathies.
For instance, the ciliopathy Jeune asphyxiating thoracic dystrophy involves the development of abnormally short ribs, accompanied by short limbs and, occasionally, the development of extra digits.
In primary ciliary dyskinesia, motile cilia are dysfunctional and fail to beat. This can lead to bronchitis resulting from the failure to clear mucus from the sufferer’s airways. Male patients with primary ciliary dyskinesia are infertile because of impaired motility of the sperm’s flagellum (as flagella and cilia are structurally similar).
Because of the limitations placed on research involving humans, Witman and Brown propose the use of model species ranging from the green alga Chlamydomonas to the house mouse to further study the role of cilia. They write, “We can anticipate that new and improved techniques will open new avenues for gaining further insight into these immensely important and ever more fascinating cell organelles.”