Every Cell Has Its Antenna

Some cilia are for motion, others are for sensing.

The classic image of eukaryotic cilia is of a paramecium covered in its motile fur. These are cilia, and they are composed of an elegant bundle of microtubules, with cross-bridging and dynein / kinesin motors. In our bodies, we have motile cilia in only a few places, like the airway epithelium, the ventricles of the brain, the female reproductive tract, the flagellum of sperm cells, and the ear, both in the middle ear epithelium and the stereocilia of the cochlea. Each of these have very specific roles, generally to move fluids around the cell, or the cell through fluids. 

Classic differential interference contrast image of a paramecium.

Cross sectional structures of a motile cilum (left) and primary, non-motile cilium (right). This 9+0 arrangement further degrades and reduces as one travels outwards to the distal end of primary cilia.

But there is another kind of cilium, called the primary cilium, (or sensory cilium), because virtually all cells have one and only one of them. These are less elegant, and generally immobile. They seem to be a relic of our free-living cellular past, but are hardly without function. There is a class of obscure diseases called ciliopathies that trace their origin to defects in primary cilia and have related and overlapping characteristics. For example, they often feature the mirror reversal of internal organs, which originates from (a lack of) directional fluid flow caused by these cilia (in their only known motile role) in very early embryogenesis. Another common feature is obesity, thought to be due to lack of critical sensing of satiety by the hypothalamus through the primary cilia of its neurons. 

All cilia contain microtubules, and also contain traveling globs called IFT, or intra-flagellar transport complexes. These move up and down the cilium, hitched to motor proteins, carrying the various proteins that make up the cilium, after they were synthesized in the endoplasmic reticulum and sent through the golgi sorting system, into vesicles addressed to the base of the cilium. So, the cilium has its own long-standing growth and internal transport system. 

Cargoes to maintain the cilium are ferried up and down the cilium in rafts.

Some of the specialized proteins of primary cilia are sensory, such as PC1, or polycystin 1, which is a sensor of fluid flow and generates critical signals, such as to mTOR, which is a global regulator of cell energy management and proliferation. The lack of signaling when there are ciliary defects causes over-stimulation of mTOR, which leads to over-proliferation in certain places, such as the kidney, causing polycystic kidney disease, another aspect of many ciliopathies.

Immunofluorescence image of the length-influencing kinase CDKL5 (bottom) and merged with another protein that is known to mark cilia (top). Note how there is only one primary cilium on this mouse fibroblast cell.

The primary cilium is so tiny and sparse that it has been difficult to study physically, despite its functional importance. It is shorter, thinner, and much less organized than motile cilia. But recent papers have shown it in both electron microscopy and fluorescence microscopy.

Electron micrographs of one primary cilium. Note how the well-organized structure at the base (left) gets thinner towards the distal end. The middle panel tracks which microtubules from the base peter out along the cilium length. Below, note the thick raft-like structures of the intraflagellar transport system.

These images show that the microtubule structure is pretty solid at the base, but then progressively degrades along the ciliary length. So, the structure is not much to write home about. It is the cilium's role as a signaling hub, probably of very ancient origin, which is its main importance in most cells. For example, a recent paper delves into CDKL5 deficiency disorder, or CDD. As the authors state, "... patients with CDD variably present with cranial facial and hand anomalies, have significant gastrointestinal dysfunction and sleep disorders along with recurrent pneumonia and respiratory disease. The affected gene is X-linked, and most patients are females. CDKL5 is a protein kinase that is conserved across ciliated organisms including the green alga Chlamydomonas reinhardtii, where CDKL5 localizes to flagella and its loss causes the flagella to be abnormally long." These genetics suggest that males with only one copy of the affected gene are dead, (one X), while females are heterozygous, and still have one good copy. 

The CDKL5 protein is located in both motile and primary cilia, and appears to restrict their length/growth, as its most obvious phenotype. It is concentrated at the base, and may restrict the activities of the intraflagellar transport system, while being transported by it as well. It is a protein kinase that likely regulates some aspect of the IFT by phosphorylating one or more IFT proteins. The authors find that CDKL5 is inhibited by another protein kinase, CDK20, which is tied to the cell cycle and cell proliferation. CDK20 is an oncogene upregulated in many cancers, thus making one more connection between cilia and the wider mechanisms of cellular growth control.

So, a tiny organelle common to all our cells is a bit like the radio antenna on our cars.. a bit antiquated and curious to look at, but still critical for some functions. It is hard to believe that its functions could not be re-engineered to happen on the plasma membrane, which has, if needed, other localization mechanisms like lipid rafts and caveolae, but design is not part of the equation here, rather, making do with and elaborating on whatever has worked in the past is always the way forward.

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