| Cilium | |
|---|---|
 | |
| Details | |
| Identifiers | |
| Latin | cilium |
| MeSH | D002923 |
| TH | H1.00.01.1.01014 |
| FMA | 67181 |
| Anatomical terms of microanatomy | |
Thecilium (pl.:cilia; from Latin cilium 'eyelid'; in Medieval Latin and in anatomy,cilium) is a short hair-likemembrane protrusion from many types ofeukaryotic cell.[1][2] (Cilia are absent inbacteria andarchaea.) The cilium has the shape of a slender threadlike projection that extends from the surface of the much larger cell body.[2] Eukaryoticflagella found onsperm cells and manyprotozoans have a similar structure to motile cilia that enables swimming through liquids; they are longer than cilia and have a different undulating motion.[3][4]
There are two major classes of cilia:motile andnon-motile cilia, each with two subtypes, giving four types in all.[5] A cell will typically have one primary cilium or many motile cilia.[6] The structure of the cilium core, called theaxoneme, determines the cilium class. Most motile cilia have a central pair of singlemicrotubules surrounded by nine pairs of double microtubules called a9+2 axoneme. Most non-motile cilia have a9+0 axoneme that lacks the central pair of microtubules. Also lacking are the associated components that enable motility including the outer and innerdynein arms, and radial spokes.[7] Some motile cilia lack the central pair, and some non-motile cilia have the central pair, hence the four types.[5][7]
Most non-motile cilia, termedprimary cilia orsensory cilia, serve solely as sensory organelles.[8][9] Most vertebrate cell types possess a single non-motile primary cilium, which functions as a cellular antenna.[10][11]Olfactory neurons possess a great many non-motile cilia. Non-motile cilia that have a central pair of microtubules are thekinocilia present onhair cells.[5]
Motile cilia are found in large numbers onrespiratory epithelial cells – around 200 cilia per cell, where they function inmucociliary clearance, and also havemechanosensory andchemosensory functions.[12][13][14] Motile cilia onependymal cells move thecerebrospinal fluid through theventricular system of thebrain. Motile cilia are also present in theoviducts (fallopian tubes) of female (therian) mammals, where they function in movingegg cells from theovary to theuterus.[13][15] Motile cilia that lack the central pair of microtubules are found in the cells of the embryonicprimitive node; termednodal cells, these nodal cilia are responsible for theleft-right asymmetry ofbilaterians.[16]
A cilium is assembled and built from abasal 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.
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.
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 isrootletin a coiled coil rootlet protein coded for by theCROCC gene.[17]
To achieve its distinct composition, the proximal-most region of the cilium consists of atransition zone, also known as theciliary 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 andChlamydomonas reinhardtii. In mammals, disruption of the transition zone reduces the ciliary abundance of membrane-associated ciliary proteins, such as those involved inHedgehog signal transduction, compromising Hedgehog-dependent embryonic development of digit number and central nervous system patterning.
Inside a cilium is amicrotubule-basedcytoskeletal core called theaxoneme. The axoneme of a primary cilium typically has a ring of nine outer microtubule doublets (called a9+0 axoneme), and the axoneme of a motile cilium has, in addition to the nine outer doublets, two central microtubule singlets (called a9+2 axoneme). This is the same axoneme type of theflagellum. The axoneme in a motile cilium acts as a scaffold for the inner and outerdynein arms that move the cilium, and provides tracks for themicrotubule motorproteins of kinesin and dynein.[2][21][22] The transport of ciliary components is carried out byintraflagellar transport (IFT) which is similar to theaxonal transport in anerve fibre. Transport is bidirectional andcytoskeletal motor proteins kinesin and dynein transport ciliary components along the microtubule tracks; kinesin in an anterograde movement towards the ciliary tip and dynein in a retrograde movement towards the cell body. The cilium has its own ciliary membrane enclosed within the surroundingcell membrane.[23]
In animals, non-motileprimary cilia are found on nearly every type of cell, blood cells being a prominent exception.[2] Most cells only possess one, in contrast to cells with motile cilia, an exception beingolfactory sensory neurons, where theodorant receptors are located, which each possess about ten cilia. Some cell types, such as retinal photoreceptor cells, possess highly specialized primary cilia.[24]
Although the primary cilium was discovered in 1898, it was largely ignored for a century and considered avestigial organelle without important function.[25][2] Recent findings regarding its physiological roles in chemosensation, signal transduction, and cell growth control, have revealed its importance in cell function. Its importance to human biology has been underscored by the discovery of its role in a diverse group of diseases caused by thedysgenesis or dysfunction of cilia, such aspolycystic kidney disease,[26]congenital heart disease,[27]mitral valve prolapse,[28] and retinal degeneration,[29] calledciliopathies.[30][31] The primary cilium is now known to play an important role in the function of many human organs.[2][10] Primary cilia on pancreaticbeta cells regulate their function and energy metabolism. Cilia deletion can lead to islet dysfunction andtype 2 diabetes.[32]
Cilia are assembled during theG1 phase and are disassembled before mitosis occurs.[33][11] Disassembly of cilia requires the action ofaurora kinase A.[34] The current scientific understanding of primary cilia views them as "sensorycellular 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[clarification needed] and enclosed by a plasma membrane continuous with the plasma membrane of the cell. For many cilia, thebasal body, where the cilium originates, is located within a membrane invagination called the ciliary pocket. The cilium membrane and the basal body microtubules are connected by distal appendages (also called transition fibers). Vesicles carrying molecules for the cilia dock at the distal appendages. Distal to the transition fibers form a transition zone where entry and exit of molecules is regulated to and from the cilia. Some of the signaling with these cilia occur through ligand binding such asHedgehog signaling.[36] Other forms of signaling includeG protein-coupled receptors including thesomatostatin receptor 3 in neurons.[37]
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]
Mammals also havemotile cilia orsecondary cilia that are usually present on a cell's surface in large numbers (multiciliate), and beat in coordinatedmetachronal waves.[40] Multiciliated cells are foundlining the respiratory tract where they function inmucociliary clearance sweeping mucus containing debris away from thelungs.[13] Each cell in the respiratory epithelium has around 200 motile cilia.[12]
In thereproductive tract,smooth muscle contractions help the beating of the cilia in moving theegg cell from the ovary to the uterus.[13][15]In theventricles of the brain ciliatedependymal cells circulate thecerebrospinal fluid.
The functioning of motile cilia is strongly dependent on the maintenance of optimal levels ofpericiliary fluid bathing the cilia.Epithelial sodium channels (ENaCs) are specifically expressed along the entire length of cilia in the respiratory tract, andfallopian tube oroviduct that apparently serve as sensors to regulate the periciliary fluid.[13][41]
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 theprimitive node. Nodal cells are responsible for theleft-right asymmetry inbilateral animals.[16] While lacking the central apparatus there aredynein arms present that allow the nodal cilia to move in a spinning fashion. The movement creates a current flow of the extraembryonic fluid across thenodal 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 thechoroid 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 cells have a single cilium called a monocilium. They are present in the very earlydevelopment of the embryo on theprimitive node. There are two areas of the node with different types ofnodal 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]
The motile cilia onsperm cells and manyprotozoans enables swimming through liquids and are traditionally referred to as "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]
Ciliates areeukaryoticmicroorganisms that possess motile cilia exclusively and use them for either locomotion or to simply move liquid over their surface. AParamecium for example is covered in thousands of cilia that enable its swimming. These motile cilia have been shown to be also sensory.[44]
Cilia are formed through the process ofciliogenesis. An early step is docking of the basal body to the growing ciliary membrane, after which the transition zone forms. The building blocks of the ciliary axoneme, such astubulins, are added at the ciliary tips through a process that depends partly onintraflagellar transport (IFT).[45][46] Exceptions includeDrosophila sperm andPlasmodium 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 themicrotubule organizing center, thebasal body. Some basal body proteins asCEP164,ODF2[48]andCEP170,[49] are required for the formation and the stability of the cilium.
In effect, the cilium is ananomachine composed of perhaps over 600 proteins in molecular complexes, many of which also function independently as nanomachines.Flexible linkers allow themobile protein domainsconnected by them to recruit their binding partners and induce long-rangeallostery viaprotein domain dynamics.[35]
Thedynein in the axoneme –axonemal dynein forms bridges between neighbouring microtubule doublets. WhenATP 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 ofnexin between the microtubule doublets. And thus the force generated by dynein is instead converted into a bending motion.[50][51]
Some primary cilia onepithelial cells in eukaryotes act ascellular antennae, providingchemosensation,thermosensation andmechanosensation 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, asecretory 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 aremotile.[52]
Someepithelial cells are ciliated, and they commonly exist as a sheet of polarized cells forming a tube or tubule with cilia projecting into thelumen. This sensory and signalling role puts cilia in a central role for maintaining the local cellular environment and may be whyciliary 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 generateleft-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]
With axo-ciliarysynapses, there is communication betweenserotonergicaxons and primary cilia ofCA1pyramidalneurons that alters the neuron'sepigenetic state in thenucleus – "a way to change what is being transcribed or made in the nucleus" via this signalling distinct from that at theplasma membrane which also is longer-term.[56][57]
Ciliary defects can lead to a number of human diseases.[31][58] Defects in cilia adversely affect many critical signaling pathways essential to embryonic development and to adult physiology, and thus offer a plausible hypothesis for the oftenmulti-symptom nature of diverse ciliopathies.[30][31] Known ciliopathies includeprimary ciliary dyskinesia,Bardet–Biedl syndrome,polycystic kidney andliver disease,nephronophthisis,Alström syndrome,Meckel–Gruber syndrome,Sensenbrenner syndrome and some forms ofretinal degeneration.[30][52] Genetic mutations compromising the proper functioning of cilia,ciliopathies, can cause chronic disorders such asprimary ciliary dyskinesia (PCD),nephronophthisis, andSenior–Løken syndrome. In addition, a defect of the primary cilium in therenal tubule cells can lead topolycystic kidney disease (PKD). In another genetic disorder calledBardet–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 thetype 2 diabetes models.[59]
Epithelial sodium channels (ENaCs) that are expressed along the length of cilia regulatepericiliary fluid level. Mutations that decrease the activity of ENaCs result in multisystempseudohypoaldosteronism, that is associated with fertility problems.[13] Incystic fibrosis that results from mutations in the chloride channelCFTR, 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 assitus inversus (a combination of findings is known asKartagener syndrome), andsitus ambiguus (also known asHeterotaxy syndrome).[61] These left-right anatomic abnormalities can also result incongenital 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]
Reduction of cilia function can also result from infection. Research intobiofilms 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 theimmature egg cell, and the embryo to theuterus forimplantation depends on the combination of regulated smooth muscle contractions, and ciliary beating. Dysfunction in this transportation can result in anectopic pregnancy where the embryo is implanted (usually) in thefallopian 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]
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 are highly ciliated.[70][71]
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