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Read more: “Instant Expert 36: Human cell tails“

Two decades ago, some biologists were still arguing that the non-beating tails found on most cell types were evolutionary leftovers. No one would make that claim today. It is now clear that these primary cilia play a key role in the development and functioning of pretty much every organ in the body. Beating tails, too, have turned out to play a bigger role than previously appreciated. Much of the evidence has come from studying hereditary disorders caused by mutations in tail genes

Tails as antennae

Why does nearly almost every kind of human cell in the body have a single, non-beating tail protruding from its surface? For decades many biologists dismissed these primary cilia as unimportant, but a few thought they must be useful. In 1985, for instance, Anthony Poole suggested that they were nothing less than “cellular cybernetic probes”. And around the turn of the century, the evidence to support this view finally began to emerge.

Inside our kidneys, fluid flows through tiny tubules. The cells lining these tubes have non-beating tails protruding from their surface, that were spotted bending in response to the speed of flow. Further work showed that this bending produces a response in the cell, in the form of an influx of calcium ions.

Meanwhile, other biologists had been studying a common genetic disorder known as polycystic kidney disease, in which large fluid-filled cysts form in the kidneys (pictured right), eventually destroying them. Its cause was traced to mutations in two proteins that form calcium channels, called polycystin-1 and 2. In 2002, it was shown that these proteins are usually found in the membrane of primary cilia, but are missing or misplaced in people with polycystic kidneys. These different strands of research pointed to a clear picture: kidney cells use their tails to sense fluid flow, and if these sensors are not working properly things go awry.

The findings made other biologists sit up and take notice. In the past decade, a series of landmark studies have shown that primary cilia can have all kinds of surprising sensory abilities. Besides fluid movement, some sense chemicals, osmotic concentration, temperature and even gravity. For instance, we detect odours through the many olfactory receptors on the primary cilia of olfactory neurons.

These sensory capabilities also turn out to be far more important than anyone imagined just a few years ago. The evidence comes from a growing list of diseases being traced to mutations in the genes coding for these sensors. The symptoms range from blindness to obesity to learning problems to kidney failure to short limbs to narrow ribs (which cause respiratory failure in infants).

The symptoms vary so much because primary cilia play a role in so many different processes. During embryonic development, for instance, cells are constantly on the move, migrating to form new tissues and organs. It is through cilia that these cells are able to sense their environment and so change their behaviour accordingly. Even in adults, the maintenance of organ function requires continuous feedback. In bone and cartilage, for example, the primary cilia detect pressure, switching on the genes needed to maintain or strengthen these tissues.

What’s more, primary cilia are more than mere sensors. One way cells talk to each other involves the so-called “hedgehog signalling pathways” – a chemical communication system that plays a vital role during development. It has recently become clear that in vertebrates, the hedgehog signalling system depends on primary cilia, with many parts of this system being found on these tails. Our inner tails, then, are not just sensory antennae but also .

“Our non-beating tails act not just as sensory antenna but also as communication hubs”

Wag this way

While non-beating tails have turned out to be crucial cellular sensors, beating tails also have unexpected roles. In our bodies, moving cilia (the brown “fur” pictured above) are found on the lining of many tubes and cavities. They help keep our windpipes and lungs clear by beating in unison 7 to 22 times a second to sweep mucus and particles along. They perform the same role in the nasal cavities and the Eustachian tube, which drains the middle ear. Beating cilia also circulate the cerebrospinal fluid around our brains and spine, and help move eggs along the fallopian tubes to the womb, where they can be fertilised by sperm swimming using their tails.

Impaired cilia cannot clear mucous properly, resulting in repeated infections of the sinus, throat, lungs and ears, and ultimately permanent lung damage. Smoking can damage cilia, for instance, while some individuals inherit genetic mutations that prevent cilia beating normally.

Very confusingly, inherited diseases caused by tails failing to beat properly are called primary ciliary dyskinesias, though they have nothing to do with primary cilia. As a rough estimate, around 1 in 32,000 people suffer from these disorders, but the true figure could be higher. In the most severe cases, the only treatment option is lung transplantation. With early diagnosis, regular physiotherapy can drastically reduce infections and slow the accumulation of permanent damage. Sadly, the disorders are often not diagnosed until a late stage.

Some people with faulty cilia not only suffer from recurrent infections and lung damage, but also have situs inversus, in which the position of the internal organs is reversed. This condition is known as Kartagener syndrome. Organs can develop in the opposite configuration – with the heart on the right and so on – without any health consequences. In other cases, not all the organs flip sides together, leading to serious problems such as heart defects or gut malrotation. For many decades, this remained a mystery. Why should people with faulty cilia also have reversed left-right symmetry?

We now know that the asymmetry of our bodies is established very early on. A few days after fertilisation of the egg, the embryo appears to be a symmetrical cylinder with a top and bottom but no left, right, front or back. Then, however, over the course of a few hours an asymmetry is established as genes are activated on one side but not on the other, and the shape of the embryo changes rapidly.

What triggers this? At one end of the embryo there is a pit, called the “node”, which is lined with cells that each have a single beating tail on their surfaces. These tails all start to sweep in a rough circle in a clockwise fashion, and this motion generates a net leftward flow. This flow establishes which side is the left and which the right, and therefore the customary position of organs, called situs solitus. The clinching evidence came in 1998, thanks to some mice in which a gene related to the growth of cilia formation had been disabled. In these mice there were no cilia on the node cells and the establishment of left-right symmetry was random, with half having reversed symmetry.

Much still remains to be discovered, however. In particular, it is unclear how this leftward flow leads to asymmetric gene activation. One idea is that the flow creates an imbalance in the level of a signalling molecule, which may be detected by non-beating cilia on cells on the periphery of the node. Another idea is that the primary cilia on the periphery sense the direction of flow rather than a concentration gradient. Either way, the establishment of asymmetry would require both kinds of tails.

This article appeared in print under the headline “Lines of communication”