Primary Cilia

A cilium (from Latin, meaning ‘eyelash’;[1] the plural is cilia) is an organelle found on eukaryotic cells and are slender protuberances that project from the much larger cell body.[2]

There are two types of cilia: motile cilia and nonmotile, or primary, cilia, which typically serve as sensory organelles. In eukaryotes, motile cilia and flagella together make up a group of organelles known as undulipodia.[3] Eukaryotic cilia are structurally identical to eukaryotic flagella, although distinctions are sometimes made according to function and/or length.[4] Biologists have various ideas about how the various flagella may have evolved.[5]

In animals, primary cilia are found on nearly every cell.[2] In comparison to motile cilia, non-motile (or primary) cilia usually occur one per cell; nearly all mammalian cells have a single non-motile primary cilium. In addition, examples of specialized primary cilia can be found in human sensory organs such as the eye and the nose: The outer segment of the rod photoreceptor cell in the human eye is connected to its cell body with a specialized non-motile cilium.[6] The dendritic knob of the olfactory neuron, where the odorant receptors are located, also contains non-motile cilia (about 10 cilia per dendritic knob).

Although the primary cilium was discovered in 1898, it was largely ignored for a century. Only recently has great progress been made in understanding the function of the primary cilium. Until the 1990s, the prevailing view of the primary cilium was that it was merely a vestigial organelle without important function.[2]

Recent findings regarding its physiological roles in chemical sensation, signal transduction, and control of cell growth, have led scientists to acknowledge its importance in cell function, with the discovery of its role in diseases not previously recognized to involve the dysgenesis and dysfunction of cilia, such as polycystic kidney disease,[7]congenital heart disease,[8] and an emerging group of genetic ciliopathies,[9] including, but not limited to the Joubert syndrome (See the Institute’s Disease Chapter)

It is also known that the cilium must be disassembled before mitosis can occur. However, the mechanisms that control this process are still largely unknown.[10]

The primary cilium is now known to play an important role in the function of many human organs.[2]

The current scientific understanding of primary cilia views them as “sensory cellular antennae that coordinate a large number of cellular signaling pathways, sometimes coupling the signaling to ciliary motility or alternatively to cell division and differentiation.”.[11]

The primary non-motile cilia has a “9+0” axonemal structure and is divided into subdomains. The entire structure is enclosed by a plasma membrane continuous with the plasma membrane of the cell. The basal body, where the cilia originates, is located within the ciliary pocket. The cilium membrane and the basal body microtubules are connected by transition fibers. Vesicles carrying molecules for the cilia dock at the transition fibers. The transition fibers form a transition zone where entry and exit of molecules is regulated to and from the cilia. Molecules can move to the tip of the cilia with the aid of anterograde IFT particles and the kinesin-2 motor. Molecules can also use retrograde IFT particles and the cytoplasmic dynein motor to move toward the basal body. Some of the signaling with these cilia occur through ligand binding such as Hedgehog signaling. Other forms of signaling include G-coupled receptors including the somatostatin receptor 3 in neuronal cells. [12]

Larger eukaryotes, such as mammals, have motile cilia as well. Motile cilia are usually present on a cell’s surface in large numbers and beat in coordinated waves.[13] In humans, for example, motile cilia are found in the lining of the trachea (windpipe), where they sweep mucus and dirt out of the lungs.[14] 
In female mammals, the beating of cilia in the Fallopian tubes moves the ovum from the ovary to the uterus.[14][15]

The functioning of motile cilia is strongly dependent on the maintenance of optimal levels of fluid bathing the cilia.

Epithelial sodium channels ENaC that are specifically expressed along the entire length of cilia apparently serve as sensors that regulate fluid level surrounding the cilia.[14][16]

Ciliates are microscopic organisms that possess motile cilia exclusively and use them for either locomotion or to simply move liquid over their surface.

Inside cilia and flagella is a microtubule-based cytoskeleton called the axoneme. The axoneme of primary cilia typically has a ring of nine outer microtubule doublets (called a 9+0 axoneme), and the axoneme of a motile cilium has two central microtubule singlets in addition to the nine outer doublets (called a 9+2 axoneme). The axonemal cytoskeleton acts as a scaffolding for various protein complexes and provides binding sites for molecular motorproteins such as kinesin II, that help carry proteins up and down the microtubules.[2][17][18] On the outside of cilia is a membrane like the plasma membrane, but compositionally distinct due to a blocking ring (“necklace”) around the base,[19] and distinct also in its population of receptors and other integral proteins.

The ciliary rootlet is a cytoskeleton-like structure that originates from the basal body at the proximal end of a cilium. It extends proximally toward the cell nucleus. Rootlets are typically 80-100 nm in diameter and contain cross striae distributed at regular intervals of approximately 55-70 nm. According to the Gene Ontology, the following proteins localize to the ciliary rootlet: amyloid precursor protein, rootletin, kinesins (KIF5B, KIF5C, KLC2, KLC3), and presenilins (PSEN1, PSEN2).[20]

Though they have been given different names, cilia and flagella have nearly identical structures and have the same purpose: motion. The movement of the appendage can be described as a wave. The wave tends to originate at the basal body and can be described in terms of frequency, amplitude and wave length. A key difference between the two structures is that in a eukaryotic organism such as humans, flagella are used to propel the cell while cilia are used to move substances across a surface. An example of each would be the flagellum present on a sperm cell and the cilium on the epithelial tissue of the lungs that clears out foreign particles. Cilia and flagella also possess the same axoneme structure of “9+2”. The 9 indicates the number of doublets present around the outer edge of the appendage while the two refers to the interior doublet. The only known exception to this is in a primary non-motile cilium, which only contains the nine outer doublets, resulting in a “9+0” axonemal structure. The beating motion is created by the sliding of outer doublets, and originates in the axoneme, not at the basal body.[21]C


Cilia are formed through the process of ciliogenesis. The building blocks of the cilia such as tubulins and other partially assembled axonemal proteins are added to the ciliary tips which point away from the cell body.[22]

In most species bi-directional motility called intraflagellar transport (IFT) plays an essential role in moving these building materials from the cell body to the assembly site.[23] IFT also carries the disassembled material to be recycled from the ciliary tip back to the cell body. By regulating the equilibrium between these two IFT processes, the length of cilia can be maintained dynamically. Disassembly of cilia requires the action of the Aurora A kinase .[24]

Exceptions where IFT is not present include Plasmodium falciparum, which is one of the species of Plasmodium that cause malaria in humans. In this parasite, cilia assemble in the cytoplasm.[25]

At the base of the cilium where it attaches to the cell body is the microtubule organizing center, the basal body. Some basal body proteins as CEP164, ODF2 [26] and CEP170,[27] regulate the formation and the stability of the cilium. A transition zone between the basal body and the axoneme “serves as a docking station for intraflagellar transport and motor proteins.”[2]

In effect, the cilium is a nanomachine composed of perhaps over 600 proteins in molecular complexes, many of which also function independently as nanomachines. Flexible linkers allow the mobile protein domains connected by them to recruit their binding partners and induce long-range allostery via protein domain dynamics.[11]

The dynein in the axoneme forms bridges between neighbouring microtubule doublets. When ATP activates the motor domain of dynein, it attempts to walk along the adjoining microtubule doublet. This would force the adjacent doublets to slide over one another if not for the presence of Nexin between the microtubule doublets. And thus the force generated by dynein is instead converted into a bending motion.[28]

Some primary cilia on epithelial cells in eukaryotes act as cellular antennae, providing chemosensation, thermosensation and mechanosensation of the extracellular environment.[29]

These cilia then play a role in mediating specific signalling cues, including soluble factors in the external cell environment, a secretory role in which a soluble protein is released to have an effect downstream of the fluid flow, and mediation of fluid flow if the cilia are motile.[29]

Some epithelial cells are ciliated, and they commonly exist as a sheet of polarized cells forming a tube or tubule with cilia projecting into the lumen.

This sensory and signalling role puts cilia in a central role for maintaining the local cellular environment and may be why ciliary defects cause such a wide range of human diseases like Joubert Syndrome.[30]

Cilia-related Diseases

Ciliary defects can lead to a number of human diseases. Genetic mutations compromising the proper functioning of cilia, ciliopathies, like Joubert Syndrome can cause chronic disorders such as primary ciliary dyskinesia (PCD), nephronophthisis or Senior-Loken syndrome. In addition, a defect of the primary cilium in the renal tube cells can lead to polycystic kidney disease (PKD). In another genetic disorder called Bardet-Biedl syndrome (BBS), the mutant gene products are the components in the basal body and cilia.[9]

Lack of functional cilia in female Fallopian tubes can cause ectopic pregnancy.

Therein, a fertilized ovum may not reach the uterus if the cilia are unable to move it there. In such a case, the ovum will implant in the Fallopian tubes, causing a tubal pregnancy, the most common form of ectopic pregnancy.[31]

As noted above, epithelial sodium channels ENaC that are expressed along the length of cilia regulate fluid level surrounding the cilia.

Mutations that decrease the activity of ENaC result in multisystem pseudohypoaldosteronism, that is associated with fertility problems.[14] In cystic fibrosis that results from mutations in the chloride channel CFTR, ENaC activity is enhanced leading to a severe reduction of the fluid level that causes complications and infections in the respiratory airways.[16]

Since the flagellum of human sperm is actually a modified cilium, ciliary dysfunction can also be responsible for male infertility.[32]

Of interest, there is an association of primary ciliary dyskinesia with left-right anatomic abnormalities such as situs inversus (a combination of findings known as Kartagener’s syndrome) and other heterotaxic defects. These left-right anatomic abnormalities can also result in congenital heart disease.[33] It has been shown that proper cilial function is responsible for the normal left-right asymmetry in mammals.[34]

Early 2000s findings in genetic research have suggested that a large number of genetic disorders, both genetic syndromes and genetic diseases, that were not previously related in the medical literature, may be, in fact, highly related in the root cause of the widely varying set of medical symptoms that are clinically visible in the disorder.

These have been grouped as an emerging class of diseases called ciliopathies. The underlying cause may be a dysfunctional molecular mechanism in the primary/immotile cilia, organelles which are present in many diverse cellular types throughout the human body.

Cilia defects adversely affect numerous critical developmental signaling pathways essential to cellular development and thus offer a plausible hypothesis for the often multi-symptom nature of a large set of syndromes and diseases.[9]

Known ciliopathies include primary ciliary dyskinesia, Bardet-Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Alström syndrome, Joubert syndrome, Meckel-Gruber syndrome, Sensenbrenner syndrome and some forms of retinal degeneration.[9][29]

Reduction of cilia function can also result from infection. Research into biofilms has been increasing and has shown how bacteria can alter cilia.

A biofilm is a community of bacteria of either the same or multiple species of bacteria. The cluster of cells secretes different factors which form an extracellular matrix. Cilia in the respiratory system is known to move mucus and pathogens out of the airways.

It has been found that patients with biofilm positive infections have impaired cilia function. The impairment may present as decreased motion or reduction in the number of cilia. Though these changes result from an external source, they still effect the pathogenicity of the bacteria, progression of infection, and how it is treated.[35]


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 External sites and Educational Videos

Brief summary of importance of cilia to many organs in human physiology

The Ciliary Proteome Web Page at Johns Hopkins

Happiness Medicine & Holistic Medicine Posts



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