Cilium

Cilium
SEM micrograph of motile cilia projecting from respiratory epithelium in the trachea
Details
Identifiers
Latin	cilium
MeSH	D002923
TH	H1.00.01.1.01014
FMA	67181
Anatomical terms of microanatomy [edit on Wikidata]

The cilium (pl.: cilia; from

A cilium is assembled and built from a basal body on the cell surface. From the basal body, the ciliary rootlet forms ahead of the transition plate and transition zone where the earlier microtubule triplets change to the microtubule doublets of the axoneme.

Basal body

The foundation of the cilium is the basal body, a term applied to the mother centriole when it is associated with a cilium. Mammalian basal bodies consist of a barrel of nine triplet microtubules, subdistal appendages and nine strut-like structures, known as distal appendages, which attach the basal body to the membrane at the base of the cilium. Two of each of the basal body's triplet microtubules extend during growth of the axoneme to become the doublet microtubules.

Ciliary rootlet

The ciliary rootlet is a cytoskeleton-like structure that originates from the basal body at the proximal end of a cilium. Rootlets are typically 80-100 nm in diameter and contain cross striae distributed at regular intervals of approximately 55-70 nm. A prominent component of the rootlet is rootletin a coiled coil rootlet protein coded for by the CROCC gene.^[17]

Transition zone

To achieve its distinct composition, the proximal-most region of the cilium consists of a transition zone, also known as the ciliary gate, that controls the entry and exit of proteins to and from the cilium.^[18][19][20] At the transition zone, Y-shaped structures connect the ciliary membrane to the underlying axoneme. Control of selective entry into cilia may involve a sieve-like function of transition zone. Inherited defects in components of the transition zone cause ciliopathies, such as Joubert syndrome. Transition zone structure and function is conserved across diverse organisms, including vertebrates, Caenorhabditis elegans, Drosophila melanogaster and Chlamydomonas reinhardtii. In mammals, disruption of the transition zone reduces the ciliary abundance of membrane-associated ciliary proteins, such as those involved in Hedgehog signal transduction, compromising Hedgehog-dependent embryonic development of digit number and central nervous system patterning.

Axoneme

Inside a cilium, is a

Cilia are assembled during the G₁ phase and are disassembled before mitosis occurs.^[33][11] Disassembly of cilia requires the action of aurora kinase A.^[34] The current scientific understanding of primary cilia views them as "sensory cellular antennae that coordinate many cellular signaling pathways, sometimes coupling the signaling to ciliary motility or alternatively to cell division and differentiation."^[35] The cilium is composed of subdomains^[

Modified non-motile cilia

Kinocilia that are found on hair cells in the inner ear are termed as specialized primary cilia, or modified non-motile cilia. They possess the 9+2 axoneme of the motile cilia but lack the inner dynein arms that give movement. They do move passively following the detection of sound, allowed by the outer dynein arms.^[38][39]

Motile cilia

microvilli on non-ciliated cells in scanning electron micrograph

.

Mammals also have motile cilia or secondary cilia that are usually present on a cell's surface in large numbers (multiciliate), and beat in coordinated metachronal waves.^[40] Multiciliated cells are found lining the respiratory tract where they function in mucociliary clearance sweeping mucus containing debris away from the lungs.^[13] Each cell in the respiratory epithelium has around 200 motile cilia.^[12]

In the

reproductive tract, smooth muscle contractions help the beating of the cilia in moving the egg cell from the ovary to the uterus.^[13][15]

In the

ependymal cells circulate the cerebrospinal fluid

.

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

periciliary fluid bathing the cilia. Epithelial sodium channels (ENaCs) are specifically expressed along the entire length of cilia in the respiratory tract, and fallopian tube or oviduct that apparently serve as sensors to regulate the periciliary fluid.^[13][41]

Modified motile cilia

Motile cilia without the central pair of singlets (9+0) are found in early embryonic development. They are present as nodal cilia on the nodal cells of the

dynein arms present that allow the nodal cilia to move in a spinning fashion. The movement creates a current flow of the extraembryonic fluid across the nodal surface

in a leftward direction that initiates the left-right asymmetry in the developing embryo. [12]^[42]

Motile, multiple, 9+0 cilia are found on the epithelial cells of the choroid plexus. Cilia also can change structure when introduced to hot temperatures and become sharp. They are present in large numbers on each cell and move relatively slowly, making them intermediate between motile and primary cilia. In addition to 9+0 cilia that are mobile, there are also solitary 9+2 cilia that stay immobile found in hair cells.^[39]

Nodal cilia

Scanning electron micrograph of nodal cilia on a mouse

embryo

Nodal cells have a single cilium called a monocilium. They are present in the very early

development of the embryo on the primitive node. There are two areas of the node with different types of nodal cilia. On the central node are motile cilia, and on the peripheral area of the node the nodal cilia are modified motile.^[42]

The motile cilia on the central cells rotate to generate the leftward flow of extracellular fluid needed to initiate the left-right asymmetry.[42]

Cilia versus flagella

See also: Flagellum § Terminology

The motile cilia on

flagella".^[3] As these protrusions are structurally identical to motile cilia, attempts at preserving this terminology include making a distinction by morphology ("flagella" are typically longer than ordinary cilia and have a different undulating motion)^[4] and by number.^[43]

Microorganisms

eukaryotic microorganisms that possess motile cilia exclusively and use them for either locomotion or to simply move liquid over their surface. A Paramecium for example is covered in thousands of cilia that enable its swimming. These motile cilia have been shown to be also sensory.^[44]

Ciliogenesis

Main article: Ciliogenesis

Cilia are formed through the process of

tubulins, are added at the ciliary tips through a process that depends partly on intraflagellar transport (IFT).^[45][46] Exceptions include Drosophila sperm and Plasmodium falciparum flagella formation, in which cilia assemble in the cytoplasm.^[47]

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^[48] and CEP170,^[49] are required for the formation and the stability of the cilium.

In effect, the cilium is a

Flexible linkers

allow the mobile protein domains connected by them to recruit their binding partners and induce long-range

allostery

via protein domain dynamics.^[35]

Function

The

axonemal dynein 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.^[50][51]

Sensing the extracellular environment

Some primary cilia on

thermosensation and mechanosensation of the extracellular environment.^[52][10] 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.^[52]

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.^[31]

In the embryo,

nodal cilia are used to direct the flow of extracellular fluid. This leftward movement is to generate left-right asymmetry across the midline of the embryo. Central cilia coordinate their rotational beating while the immotile cilia on the sides sense the direction of the flow.^[42][53][54] Studies in mice suggest a biophysical mechanism by which the direction of flow is sensed.^[55]

Axo-ciliary synapse

With axo-ciliary

plasma membrane which also is longer-term.^[56][57]

Clinical significance

Main article: Ciliopathy

Ciliary defects can lead to a number of human diseases.

multi-symptom nature of diverse ciliopathies.^[30][31] Known ciliopathies include primary ciliary dyskinesia, Bardet–Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Alström syndrome, Meckel–Gruber syndrome, Sensenbrenner syndrome and some forms of retinal degeneration.^[30][52] Genetic mutations compromising the proper functioning of cilia, ciliopathies, can cause chronic disorders such as primary ciliary dyskinesia (PCD), nephronophthisis, and Senior–Løken syndrome. In addition, a defect of the primary cilium in the renal tubule 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.^[30] Defects in cilia cells are linked to obesity and often pronounced in type 2 diabetes. Several studies already showed impaired glucose tolerance and reduction in the insulin secretion in the ciliopathy models. Moreover, the number and length of cilia was decreased in the type 2 diabetes models.^[59]

periciliary fluid level. Mutations that decrease the activity of ENaCs result in multisystem pseudohypoaldosteronism, that is associated with fertility problems.^[13] 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.^[41]

Since the flagellum of human sperm has the same internal structure of a cilium, ciliary dysfunction can also be responsible for male infertility.[60]

There is an association of primary ciliary dyskinesia with left-right anatomic abnormalities such as

congenital heart disease.^[62] It has been shown that proper cilial function is responsible for the normal left-right asymmetry in mammals.^[63]

The diverse outcomes caused by ciliary dysfunction may result from alleles of different strengths that compromise ciliary functions in different ways or to different extents. Many ciliopathies are inherited in a Mendelian manner, but specific genetic interactions between distinct functional ciliary complexes, such as transition zone and BBS complexes, can alter the phenotypic manifestations of recessive ciliopathies.[64]^[65] Some mutations in transition zone proteins can cause specific serious ciliopathies.^[66]

Extracellular changes

Reduction of cilia function can also result from infection. Research into biofilms has shown that 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.^[67]

The transportation of the

implantation depends on the combination of regulated smooth muscle contractions, and ciliary beating. Dysfunction in this transportation can result in an ectopic pregnancy where the embryo is implanted (usually) in the fallopian tube before reaching its proper destination of the uterus. Many factors can affect this stage including infection and menstrual cycle hormones. Smoking (causing inflammation), and infection can reduce the numbers of cilia, and the ciliary beat can be affected by hormonal changes.^[15][68]

Primary cilia in pancreatic cells

The pancreas is a mixture of highly differentiated exocrine and endocrine cells. Primary cilia are present in exocrine cells which are centroacinar, duct cells.[69]^[32] Endocrine tissue is composed of different hormone secreting cells. Insulin secreting beta cells and glucagon secreting alpha cells which are highly ciliated.^[70][71]

See also

• Biological machines
• Protein domain dynamics
• Protein flexibility
• Stereocilia

References

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External links

• Brief summary of importance of cilia to many organs in human physiology
• The Ciliary Proteome Web Page at Johns Hopkins