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Cilia, development and disease

Cilia are small, hair-like extensions that protrude out from the cell surface, and are essential for a wide range of processes in the body. We are interested in what happens when cilia malfunction and the impact defective cilia have on both embryonic development and adult disease.

Cilia can be thought of in two classes; motile cilia, which are restricted to a small number of specialised cells (such as in the trachea), and immotile cilia, which are present on most cell types and are known to function in sensation of various different types of signal.

The best known example of motile cilia are those found in the lungs, where they play a vital role in clearing mucus, carrying with it the dust and dirt we inhale. In smokers, these cilia often become paralysed, which is one reason why heavy smokers tend to develop a hacking cough. Motile cilia help to drive the flow of cerebrospinal fluid around the brain. The sperm tail, normally called its flagellum, is actually a very long motile cilium. Motile cilia are also present in the female reproductive tract, where they aid in the transport of the egg towards the womb.

Immotile cilia, also called primary cilia, serve an altogether different role. They facilitate certain kinds of sensation by cells (such as urine flow in the kidney), and are involved in a number of signalling pathways, including the Hedgehog, Wnt and PDGF pathways. Cilia are also known to play a role in our senses of sight, taste and smell. As might be predicted from all of these roles, defects in cilia function lead to human disease. Indeed, a diverse collection of diseases known as the ciliopathies result from problems with cilia. These show a wide variety of signs and symptoms that impact many aspects of body patterning and function.

Cilia and left-right patterning

One area that we are particularly interested in is how our bodies achieve left-right asymmetric placement of our organs, such as the heart and lungs. When this goes wrong, some individuals simply show a mirror-image, left-right pattern with all of the organ positions reversed (the heart, for example, will be on the right-hand side rather than the left). This is known as situs inversus and can remain undiagnosed until a patient undergoes a scan or even surgery. More worrying is heterotaxy, where the left-right position of each organ appears to be independently established; this usually leads to very serious congenital heart defects.

Left-right patterning is first established in a small pit, called the node, present in the early embryo. Here, the rotational beating of motile cilia drives fluid leftwards across the node. This leftward fluid flow is the first left-right asymmetry event in the embryo. Immotile cilia on the cells surrounding this pit respond to the flow as it reaches the left side, leading to the first left-right asymmetry in cells. The mechanism by which flow is detected remains unclear.

We are investigating the genes Pkd1l1, encoding a putative flow receptor, and Pkd2 which encodes a calcium channel, both of which localise to the immotile cilia, to figure out whether the immotile cilia specify left and right by responding to signalling molecules or to the force of the flow.

Primary ciliary dyskinesia

Motile cilia contain motor protein complexes that drive their motion. Defects in these motors result in immotile or abnormally motile cilia, leading to the human disorder primary ciliary dyskinesia (PCD). PCD causes defects in mucus clearance from the lungs, resulting in coughing, increased infection rates and ultimately lung damage if left untreated.

The presence of motile cilia in the nasal sinuses and the eustacian tubes lead to PCD patients suffering chronic rhinitis and sinusitis as well as increased incidence of otitis media. Male infertility can result from immotile sperm tails (although such infertility can be overcome by the modern fertility treatment intra-cytoplasmic sperm injection). The impact on female fertility remains less clear, although there are strong claims of an increased risk of ectopic pregnancy.

In collaboration with a human PCD clinic, we have developed a model of PCD in the mouse, allowing us to study the condition in more depth and ultimately to evaluate potential treatments.