Through these cilium-dependent signaling pathways, primary cilia play key roles in the regulation of cell division, proliferation, and signal transduction and are thus crucial in tissue and organ development and normal mammalian physiology Lancaster and Gleeson, ; Goetz and Anderson, ; Joukov and De Nicolo, ; Nachury and Mick, Moreover, primary cilia can act as a portal connecting the organism to the environment Falk et al.
Some primary cilia with specialized structures and functions have been characterized in sensory cells, which can transduce external physical or chemical signals, such as smell and visual signals, to electrical signals in mammalian olfactory and vision systems Falk et al. Kinocilia are specialized primary cilia present in auditory hair cells HCs in the inner ear. These cilia do not directly mediate auditory mechano-electrical transduction MET , but partially retain the characteristics of motility responsible for the response of HCs to sound stimuli.
Genetic mutations affecting ciliary proteins can lead to diseases in multiple organs, collectively known as ciliopathies. Therefore, maintaining stable morphology and structure of kinocilia is essential to normal physiology and their dysfunction results in corresponding sensory ciliopathies. In this review, we describe the structure, function, and degeneration of kinocilia present in the mammalian auditory system and discuss if they are promising therapeutic targets for hearing deficits.
The mammalian ear consists of the outer, middle, and inner ears, the latter consisting of the vestibular system and the cochlea. The former is sensitive to position signals mainly caused by linear acceleration and head rotation, and the latter mediates the conversion of vibrations into nerve impulses in response to sound Liu et al.
Both of these two systems have their own sensory epithelium, on which exist a large number of HCs that underpin both balance sensation and hearing. In the vestibular system, the sensory epithelium organizes as a repeating mosaic which consists of supporting cells and type I and type II HCs that differ in morphology and physiology Warchol et al.
However, the cochlea, a structure unique to mammals, has a more delicate sensory epithelium, also known as the organ of Corti. All of the HCs are highly differentiated and polarized, and each acts as a mechano-electrical transducer that turns physical signals into electrical signals. Finally, physical signals turn into electrical signals, which then pass through spiral ganglion neurons via the cochlear nerve, and the sensory signal ultimately reaches the cortex via the auditory pathway Fettiplace, ; Ashmore, The apical surface of HCs are arranged as a unique subset by a single row of IHCs and a triple row of OHCs, each of which is surrounded by a variety of non-sensory support cells based on their location relative to the spiral ganglion Elliott et al.
The OHCs are located on the lateral non-neural side and are mainly responsible for amplifying acoustic vibrations through periodic contraction and elongation of the cell body driven by changes in membrane potential.
The IHCs are located on the medial neural side, where they integrate and transmit sound signals to neurons. Synergy between these two types of cells greatly improves the resolution and sensitivity of sound signal processing Fettiplace, Figure 1. Schematic representation of the cochlear hair cells and hair bundles.
Two types of hair cells responsible for mechano-electrical transduction and auditory sensing are present in the cochlea. The stair-like W or V-shaped hair bundle appears on the apical plasma membrane of each inner hair cell and outer hair cell, collectively.
Each hair bundle contains plenty of stereocilia and a kinocilium near the corner of them, and the kinocilium degenerates after maturation of hair cells, indicating the acquisition of hearing. In newborn mice, the top of each HC possesses dozens to hundreds of actin filament-based stereocilia of increasing height arranged in a stepped V or W shape Figure 1.
A true microtubule-based cilium that is about the same height as the tallest row of stereocilia, called the kinocilium, is found near the corner of this arrangement, i. The stereocilia and kinocilium of each HC are collectively termed the hair bundle Figure 1.
Adjacent stereocilia are connected by several types of connecting protein including tip links, horizontal top connectors, shaft connectors, and ankle links Goodyear et al. Similarly, the kinocilium and adjacent stereocilia are connected by kinocilial links, while in some HCs, the kinocilia are physically separated from stereocilia Avan et al. However, although it has outer dynein arms and radial spokes, it does not have inner dynein arms Figure 2 ; Kikuchi et al.
Therefore, the outer dynein arms allow the kinocilia retaining some motor function to passively swing with the rhythmic vibration rather than through autonomous movement that requires inner dynein arms Spoon and Grant, Figure 2.
Model of the kinocilium and its cross section. However, a lack of inner dynein arms renders the lack of motor function. After the kinocilium degenerates, stereocilia mediate the entire mechano-electrical transduction MET process. When sound waves are transmitted to the cochlea, the shearing motion caused by lymph flow drives the passive swing of the hair bundle and sound signal processing.
Mammalian kinocilia mediate HC morphogenesis and PCP, and the latter dictates the proper arrangement of stereocilia that is required for hearing. In mouse cochlear HCs, kinocilium development is complete around embryonic day 15 E15 , after which time they move to the non-neural side of the cell with the basal body. Meanwhile, nearby stereocilia gradually grow to form the three rows of stair-like and V-shaped stereocilia of different heights around E17, together forming the hair bundle Williams et al.
Kinocilium develops before stereocilia, finally leading the hair bundle facing toward the non-neural side. In this way, the kinocilia play vital roles in the maturation of HCs. The MET apparatuses are located at the top of stereocilia. The hair bundle tilts toward the longer stereocilia when receiving the sound stimulus, and the tip links are stretched, leading to the opening of MET channels and the subsequent depolarization of HCs. Therefore, the stereocilia completely determine the MET activity of mature HCs, so the kinocilium, which dictates the proper arrangement of stereocilia that is required for hearing, must form correctly during the initial stages of HC differentiation.
Mutations in some ciliary genes encoding important intraflagellar transport IFT proteins such as Ift88 can also cause hearing defects.
Ift88 conditional knockout mice exhibit shortened cochlear ducts with multiple extra rows of HCs at the apex, severe hair bundle polarity defects, and premature differentiation of HCs Moon et al. Other studies have shown that the phenotypes of these knockout mice all include kinocilium loss, disorderly arrangement of stereocilia of different lengths, short and collapsed structural defects, and mislocation of centrosomes Tarchini and Lu, Furthermore, some genes such as Alms1 encoding proteins associated with centrosomes and ciliogenesis also show abnormal phenotypes in knockout mice, especially the mass loss of OHCs Jagger et al.
These data indicate that kinocilia play key roles in the correct orientation of stereocilia and consequently the normal function of HCs.
Moreover, some ciliopathy related genes encoding connecting proteins can cause hearing dysfunction. Mutation of Dcdc2a , which is related to the autosomal recessive deafness and encodes a protein located in the kinocilium, shows deficiency in the regulation of kinocilial ciliogenesis and length, and abnormal cohesion of the kinocilial microtubule core Grati et al.
Although kinocilia can be observed in newborn mouse cochlea HCs, they gradually degenerate in HCs from the bottom to the top of the cochlea after mice gain hearing at about postnatal day 8 P8 and completely disappear at about P12, but the basal body still remains in mature HCs Leibovici et al. The physiological significance of this cochlear degeneration is still not fully understood, but we can gain insights through comparison of cochlear kinocilia with those in the vestibular system.
When the head inclines or the body accelerates, the otolith shifts due to the effects of gravity, thereby moving kinocilia to one side through kinociliary links Day and Fitzpatrick, When the vestibular stimulus disappears, the stereocilia pull the kinocilium in the opposite direction, restoring the cell membrane to its resting potential Jacobo and Hudspeth, Surprisingly, although kinocilia are not present in the HCs of the mature cochlea, the stereocilia bundle, after being mechanically stimulated, still oscillates toward the original position of the kinocilium, consistent with the behavior of HCs in the vestibular system Fettiplace, Similar to the kinocilium and otolith, the tip of the longest stereocilium in the cochlear HC is anchored to the tectorial membrane above.
Structurally, it appears that these stereocilia are substitutes for the vestibular kinocilium. So, do the longest stereocilium and tectorial membrane also have a similar pull-in pattern? The role of the tectorial membrane in the cochlea helps us to understand this pattern.
This membrane links the longest stereocilium of each OHC via otogelin, otogelin-like, and stereocilin proteins Avan et al. When sound waves transmit from the perilymph to endolymph, they pass through the basilar membrane as traveling waves, converting vibration to the tectorial membrane via periodic compression at the top of the HC protein network.
The relative displacement of both leads to radial fluid flow in a narrow space, a shearing motion, which results in stereocilia movement in the horizontal direction and finally causing stereocilia to tilt Guinan, Presumably, kinocilia are not needed for auditory signal processing in the cochlea, since the longest stereocilia play a very similar role.
As mentioned above, the cochlea is unique to mammals, and its internal mechanical receptors have correspondingly evolved in structure and function. Primitive vertebrates such as fish only have an inner ear, which is mainly used for balance. Moreover, although they have a complete vestibular system, auditory functions must be taken into account Whitfield, Amphibians such as frogs have evolved a middle ear with an eardrum Mason et al.
In most reptiles, the ear develops further with an internal eardrum, giving rise to a prototypic external auditory canal Schwab et al. While the ears of birds and mammals differ greatly, they still have highly developed outer, middle, and inner ears. Nucleus, 2. Stereocilia, 3. Cuticular plate, 4. Radial afferent ending dendrite of type I neuron , 5. Lateral efferent ending, 6. Medial efferent ending, 7. Spiral afferent ending dendrite of type II neuron.
In both cases 3 rows of stereocilia of graded length, linked to each other, are embedded in a glabrous i. Stereocilia around a hundred are generally arranged in three rows of graded lengths. In addition to thin tip links shown here in red which are involved in the mechano-transduction process, stereocilia are attached by transverse lateral links, both in the same row and from row to row.
With transmission electron microscopy TEM , the tip link red arrow and a lateral link blue arrow between medium and tall stereocilia are clearly visible. At both ends of the tip link, a membrane condensation is seen. Bending the cilia in the opposite direction closes the channels and decreases afferent activity. Bending the cilia to the side has no effect on spontaneous neural activity.
The auditory system changes a wide range of weak mechanical signals into a complex series of electrical signals in the central nervous system. Sound is a series of pressure changes in the air. Sounds often vary in frequency and intensity over time. Humans can detect sounds that cause movements only slightly greater than those of Brownian movement. Obviously, if we heard that ceaseless except at absolute zero motion of air molecules we would have no silence. The pinna and external auditory meatus collect these waves, change them slightly, and direct them to the tympanic membrane.
The resulting movements of the eardrum are transmitted through the three middle-ear ossicles malleus, incus and stapes to the fluid of the inner ear. The footplate of the stapes fits tightly into the oval window of the bony cochlea. The inner ear is filled with fluid. Since fluid is incompressible, as the stapes moves in and out there needs to be a compensatory movement in the opposite direction.
Notice that the round window membrane, located beneath the oval window, moves in the opposite direction.
Because the tympanic membrane has a larger area than the stapes footplate there is a hydraulic amplification of the sound pressure. Also because the arm of the malleus to which the tympanic membrane is attached is longer than the arm of the incus to which the stapes is attached, there is a slight amplification of the sound pressure by a lever action.
These two impedance matching mechanisms effectively transmit air-born sound into the fluid of the inner ear. If the middle-ear apparatus ear drum and ossicles were absent, then sound reaching the oval and round windows would be largely reflected.
The cochlea is a long coiled tube, with three channels divided by two thin membranes. The top tube is the scala vestibuli, which is connected to the oval window. The bottom tube is the scala tympani , which is connected to the round window. The middle tube is the scala media, which contains the Organ of Corti. The Organ of Corti sits on the basilar membrane, which forms the division between the scalae media and tympani. The three scalae vestibuli, media, tympani are cut in several places as they spiral around a central core.
The tightly coiled shape gives the cochlea its name, which means snail in Greek as in conch shell. As explained in Tonotopic Organization , high frequency sounds stimulate the base of the cochlea, whereas low frequency sounds stimulate the apex. This feature is depicted in the animation of Figure The activity in Figure The moving dots are meant to indicate afferent action potentials.
Low frequencies are transduced at the apex of the cochlea and are represented by red dots. High frequencies are transduced at base of the cochlea and are represented by blue dots. A consequence of this arrangement is that low frequencies are found in the central core of the cochlear nerve, with high frequencies on the outside.
Sound waves cause the oval and round windows at the base of the cochlea to move in opposite directions See Figure This causes the basilar membrane to be displaced and starts a traveling wave that sweeps from the base toward the apex of the cochlea See Figure The traveling wave increases in amplitude as it moves, and reaches a peak at a place that is directly related to the frequency of the sound. The illustration shows a section of the cochlea that is moving in response to sound.
The traveling wave causes the basilar membrane and hence the Organ of Corti to move up and down. The organ of Corti has a central stiffening buttress formed by paired pillar cells. Hair cells protrude from the top of the Organ of Corti.
A tectorial roof membrane is held in place by a hinge-like mechanism on the side of the Organ of Corti and floats above the hair cells. As the basilar and tectorial membranes move up and down with the traveling wave, the hinge mechanism causes the tectorial membrane to move laterally over the hair cells. This lateral shearing motion bends the cilia atop the hair cells, pulls on the fine tip links, and opens the trap-door channels See Figure The influx of potassium and then calcium causes neurotransmitter release, which in turn causes an EPSP that initiates action potentials in the afferents of the VIIIth cranial nerve.
Most of the afferent dendrites make synaptic contacts with the inner hair cells. There are two types of hair cells, inner and outer. There is one row of inner hair cells and three rows of outer hair cells. Most of the afferent dendrites synapse on inner hair cells. Most of efferent axons synapse on the outer hair cells.
The outer hair cells are active. They move in response to sound and amplify the traveling wave.
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