Syndromic hearing loss pdf,buzzing sound in wireless headphones flipkart,sinus infection 7 year old review - Review

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One of the most common birth defects is hearing loss or deafness (congenital), which can affect as many as three of every 1,000 babies born. The most common and useful distinction in hearing impairment is syndromic versus non-syndromic. Non-syndromic hearing impairment accounts for the vast majority of inherited hearing loss, approximately 70 percent. Syndromic (sin-DRO-mik) means that the hearing impairment is associated with other clinical abnormalities. Genes are a road map for the synthesis of proteins, which are the building blocks for everything in the body: hair, eyes, ears, heart, lung, etc. Autosomal Dominant Inheritance: For autosomal dominant disorders, the transmission of a rare allele of a gene by a single heterozygous parent is sufficient to generate an affected child. Autosomal Recessive Inheritance: An autosomal recessive trait is characterized by having parents who are heterozygous carriers for mutant forms of the gene in question but are not affected by the disorder. X-linked Inheritance: A male offspring has an X chromosome and a Y chromosome, while a female has two copies of the X chromosome only. Mitochondrial Inheritance: Mitochondrias, small powerhouses within each cell, also contain their own DNA.
In the last decade, advances in molecular biology and genetics have contributed substantially to the understanding of development, function, and pathology of the inner ear. Goltz syndrome (305600), also called focal dermal hypoplasia, may have similar skin and ocular findings but the limb anomalies are not found in the disorder described here.  Goltz syndrome (305600) is the result of mutations in PORCN at another locus on the X chromosome and is thus unrelated.
Indrieri A, van Rahden VA, Tiranti V, Morleo M, Iaconis D, Tammaro R, D'Amato I, Conte I, Maystadt I, Demuth S, Zvulunov A, Kutsche K, Zeviani M, Franco B. Wimplinger I, Morleo M, Rosenberger G, Iaconis D, Orth U, Meinecke P, Lerer I, Ballabio A, Gal A, Franco B, Kutsche K.
OverviewThe earThe auditory system bears one of the most intricate mechanisms of sensation ability in humans.
Genetics of deafnessGiven the complexity of the hearing mechanism, it should come as no surprise that a panoply of genes have been discovered to be involved in hearing loss. Alicia Hutchins received her Doctorate in Audiology in 2006 from the Pennsylvania College of Optometry, School of Audiology.
Kristen Wessel received her Doctorate in Audiology in 2015 from the University of Louisville following the completion of a one year clinical externship at the Bay Pines VA Medical Center in Bay Pines, FL. Current treatments for hearing loss, the most common neurosensory disorder, do not restore perfect hearing.
Individuals without any known genetic defect may also lose hair cells due to an accumulation of acquired environmental insults, ranging from loud noises to ototoxic drugs to aging.
Prior to 2011, our knowledge of Myc in the inner ear was limited and the following descriptions of Myc interacting partners remain to be confirmed in the ear. Please use newer version of your browser or visit Internet Explorer 6 countdown page for more information. Inherited genetic defects play an important role in congenital hearing loss, contributing to about 60 percent of deafness occurring in infants. Autosomal- recessive inheritance is responsible for about 80 percent of cases of non-syndromic hearing impairment, while autosomal-dominant genes cause 20 percent, less than two percent of cases are caused by X-linked and mitochondrial genetic malfunctions. Some aspects may be expressed in a range from mild to severe or different combinations of associated symptoms may be expressed in different individuals carrying the same mutation within a single pedigree. A heterozygous parent has two types of the same gene (in this case, one mutated and the other normal) and can produce two types of gametes (reproductive cells). Interestingly, the sperm does not have any mitochondria, and consequently, only the mitochondria in the egg from the mother can be passed from one generation to the next.
Researchers have identified several of the various genes responsible for hereditary deafness or hearing loss, most notably the GJB2 gene mutation. Mutations in COX7B Cause Microphthalmia with Linear Skin Lesions, an Unconventional Mitochondrial Disease.
HCCS loss-of-function missense mutation in a female with bilateral microphthalmia and sclerocornea: a novel gene for severe ocular malformations? Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome.
Microphthalmia with linear skin defects syndrome in a mosaic female infant with monosomy for the Xp22 region: molecular analysis of the Xp22 breakpoint and the X-inactivation pattern. The inner ear, a fluid-filled organ, is responsible for transforming the mechanical energy of the sound waves into electrical stimuli, which will eventually be translated in the brain. To date, more than 50 genes and 80 additional loci have been linked to various degrees of hearing impairment (Figure 2). The clinical heterogeneity of hearing loss is characterized by common classifications based on several parameters such as onset, severity and the presence of additional clinical manifestations other than deafness.
She earned her Bachelor of Science degree in Communication Disorders from the University of Kentucky. She has been practicing Audiology since receiving her master's degree in 1999 from the University of Maryland's Department of Speech and Hearing Sciences. Hutchins is licensed by the Maryland Board of Examiners for audiologists and is a fellow of the American Academy of Audiology (AAA). Regeneration of lost organ of Corti hair cells through forced cell cycle re-entry of supporting cells or through manipulation of stem cells, both avenues towards a permanent cure, require a more complete understanding of normal inner ear development, specifically the balance of proliferation and differentiation required to form and to maintain hair cells.
Introduction Hearing Loss Is a Worldwide Problem with No Perfect SolutionHearing loss afflicts over 500 million people worldwide, including half of individuals over the age of 65 and 3 in every 1,000 births totaling 16 million children [1], making hearing loss the most common neurosensory disorder. Excluding local sound effects, hair cell loss typically progresses from base to apex (high to low frequency) and from outer to inner hair cells.
Current treatment to restore hearing is centered on the use of auditory prostheses; however, no current option is able to fully restore normal hearing (dashed line).
Proliferation Is Essential to Regeneration of Organ of Corti Hair CellsAttempts to regenerate lost hair cells recapitulate to a variable degree normal inner ear development and thus necessitate that normal development is understood to the extent that critical steps can be incorporated into attempts to regenerate hair cells. The inner ear begins as an undifferentiated patch of ectoderm adjacent to the hindbrain at embryonic day (E) 8. Upon activation of Notch by Jagged or Delta, the Notch IntraCellular Domain (NICD) is cleaved by ?-secretase. It is this very gap in knowledge compared to what is known about the Mycs elsewhere in the body to the role it may play in the inner ear that prevents the safe manipulation of Myc for therapeutic benefit in patients with hearing loss. Although exact data is not available, it is likely that genetics plays an important role in hearing loss in the elderly.
Over 400 syndromes are known to include hearing impairment and can be classified as: syndromes due to cyotgenetic or chromosomal anomalies, syndromes transmitted in classical monogenic or Mendelian inheritance, or syndromes due to multi-factorial influences, and finally, syndromes due to a combination of genetic and environmental factors.
An example of variable expressivity is seen in families transmitting autosomal dominant Waardenburg syndrome. If the inherited genes are defective, a health disorder such as hearing loss or deafness can result. One gamete will carry the mutant form of the gene of interest, and the other the normal form. This leads to an interesting inheritance pattern where only affected mothers (and not affected fathers as their sperms do not have mitochondria) can pass on a disease from one generation to the next. As one of the most common genetic causes of hearing loss, GJB2-related hearing loss is considered a recessive genetic disorder because the mutations only cause deafness in individuals who inherit two copies of the mutated gene, one from each parent.
Taking advantage of standardized nomenclature, a common classification of the loci and genes for hearing impairment has been established (HUGO Gene Nomenclature Committee).
Hearing loss that occurs prior to speech acquisition is termed prelingual deafness, either congenital or appearing after birth.
She has been practicing audiology since receiving her master's degree in 2005 from the University of Massachusetts-Amherst.
She is also nationally certified by the American Speech-Language-Hearing Association (ASHA) and is a fellow of the American Academy of Audiology (FAAA). She earned her Bachelor of Science degree in Speech-Language Pathology and Audiology from Towson University in 2005.
She is nationally certified by the American Speech-Language-Hearing Association (ASHA) and is licensed by the Maryland Board of Examiners for Audiologists.
She is also nationally certified by the American Speech-Language Hearing Association (ASHA). Her professional interests include newborn hearing assessments, pediatric and adult diagnostics, assistive listening technology, and electrophysiology.
Wessel gained experience in adult hearing evaluations, adult hearing aid fittings and repairs, electrophysiological testing, aural rehabilitation and progressive tinnitus management strategies.
She is nationally certified by the American Speech-Language Hearing Association (ASHA) and is a fellow of the American Academy of Audiology (FAAA). Direct successful alterations to the cell cycle result in cell death whereas regulation of upstream genes is insufficient to permanently alter cell cycle dynamics. Aside from these staggering figures, individuals with hearing loss carry heavy social, economic, and quality of life burdens [2]. Sound waves hit the ear drum and are turned into physical vibrations that are propagated through three middle ear bones, the malleus, the incus, and the stapes. In a restricted number of cases, hair cell loss may be partially prevented with hearing protection such as ear plugs. Thus, perfect solutions to this growing problem include prevention of hair cell loss and when hair cell loss does occur, regeneration of damaged tissue is needed to restore full functionality. Surprisingly, one of the least studied networks in organ of Corti hair cell formation is the delicate control of proliferation that is essential for transforming a handful of naive ectodermal cells into countless differentiated cells. Through induction by diffusible factors such as the Wnts and Fgfs, neuroectoderm is formed. Despite tremendous progress in the past two decades, this decision making process is not yet defined to the level that will enable translational medicine to provide therapeutic options to those suffering from hearing loss [66].


NICD translocates to the nucleus to form a complex with RBPJ to positively regulate the transcription of the Hes family of bHLH TFs [63]. To this end, many genes expressed in the ear play a different function elsewhere in the body (for example, Atoh1 initiates differentiation of hair cells in the ear but controls proliferation in the cerebellum), making a detailed functional study of the Myc network necessary before any translational application can be attempted. Inherited genetic defects are just one factor that can lead to hearing loss and deafness, both of which may occur at any stage of a person’s lifespan. Within the same family, some affected members may have dystopia canthorum (an unusually wide nasal bridge due to sideways displacement of the inner angles of the eyes), white forelock, heterochromia irides (two different-colored irises or two colors in the same iris), and hearing loss, while others with the same mutation may only have dystopia canthorum.
Sensitivity to aminoglycoside antibiotics can be inherited through a defect in mitochondrial DNA and is the most common cause of deafness in China! While the auditory system is responsible for sound sensation, the vestibular system is responsible for three dimensional orientation and gravity perception. Depending on the inheritance mode, the nonsyndromic genes or loci are classified accordingly: DFNA (dominant), DFNB (recessive), DFNX (X-linked), DFNY (Y-linked), and DFNM (modifier).
A hearing disability that appears early in childhood can have a major consequence on language acquisition. Adams worked as a pediatric and educational audiologist at the New York Eye and Ear Infirmary after completing her one year clinical fellowship at Sunshine Cottage School for Deaf Children in San Antonio, Texas. She earned a Bachelor of Science degree in Communication Science Disorders in 2011 from Ole Miss. The Myc gene family is uniquely situated to synergize upstream pathways into downstream cell cycle control. In normal hearing individuals, sound waves enter the external ear canal to cause physical vibrations of the tympanic membrane (ear drum).
The stapes articulates with the oval window, which separates the middle ear from the inner ear’s fluid-filled scala vestibuli.
In the majority of cases, the damage is unexpected, cumulative, or otherwise unpreventable (for example cisplatin treatment). To successfully prevent the loss of hair cells or regenerate hair cells after loss, we must have a greater understanding of the molecular basis of ear development, specifically, what genes are needed to form and to maintain hair cells.
Understanding this process and how it fits into overall ear development may be the critical step in both forming precursor populations of the proper size and forcing cell cycle re-entry, in either case, priming cells to regenerate functional hair cells from damaged tissue and restore hearing. As discussed earlier, it is the understanding of the initial balance of proliferation and differentiation (from which the remainder of steps is incumbent upon) that is perhaps the most important in providing long-term therapeutic intervention; yet, it remains sparsely studied.
Other factors may include: medical problems, environmental exposure, trauma, and medications. Thus the chance that the offspring of a parent with an autosomal dominant gene will develop the disorder is 50 percent.
In general, only one of the two X chromosomes carried by a female is active in any one cell while the other is rendered inactive.
Screening tests for the GJB2 gene are available for at risk individuals to help them determine their risk of having a child with hearing problems. The similarities between these two systems often leads to balance disorders in hearing impaired individuals. Additional specific symbols are used for different forms of hearing loss including otosclerosis (OTSC), auditory neuropathy (AUNA), and mitochondrial (MRTNR, MTTS) genes. Age related hearing loss (ARHL) affects the elderly population with high prevalence and its appearance and progression is influenced by both genetic and environmental factors. Scully completed her post master's clinical fellowship year at the University of Michigan Medical Center in the Department of Otolaryngology & Audiology in 2006.
Her professional interests include assistive listening technology, electrophysiology, hearing aids, and pediatrics. Her professional interests include tinnitus, amplification devices, assistive listening technology, custom hearing protection and aural rehabilitation. These vibrations are propagated through the three middle ear ossicles, the last of which, the stapes, articulates with the perilymphatic fluid-filled scalae of the inner ear. Physical vibrations of the middle ear bones are converted into compression and rarefaction of the perilymphatic fluid. In summary, SNHL is prevalent, irreversible, multi-factorial, and mostly unpreventable given human habits, leading to a global problem affecting hundreds of millions of people without bias towards race, ethnicity, or gender.
Upon elucidating these minimal essential factors, it may be possible to directly target inner ear tissues.
Once activated, Myc interacts with partner proteins to regulate a number of downstream effectors, including the cyclins, E2Fs, IDs, CDKIs, and various microRNAs. Overall, offspring of these two parents will face a 25 percent chance of inheriting the disorder. This is why when a female inherits a defective gene on one X chromosome, the normal gene on the other X chromosome can usually compensate. For each locus, the relevant symbol is depicted with a number next to it, designated by the chronological order of its discovery. About 60% of the population over the age of 65 suffers from different degrees of hearing loss, with a decline in sensitivity to sound, accompanied with reduced speech perception. During this time, she completed rotations in hearing aids, pediatrics, cochlear implants, vestibular testing, intraoperative monitoring, electrophysiology, and newborn hearing screening.
The function of the two ear expressed Mycs, N-Myc and L-Myc were unknown less than two years ago and their therapeutic potentials remain speculative.
The vibrations of the stapes cause perilymphatic fluid pressure waves to vibrate the basilar membrane. In the case of prevention, increasing the hair cell’s natural maintenance mechanisms may be sufficient. An initially small population of NS precursor cells undergoes symmetric division leading to additional NS precursor cells. This regulation leads to the inhibition of class II bHLH TFs from binding to the E-proteins which then allows the Hes family to occupy the E-proteins. As males only have one copy of the X chromosome, any defective gene is more likely to manifest into a disorder. Routinely updated, the Hereditary Hearing Loss Homepage provides an open and reliable resource for all listed genes and loci.Causes of hearing lossSimilar to other sensory loss, hearing impairment has a wide spectrum of etiologies originating from both environmental and genetic factors. Hearing loss is also categorized based on the frequency loss and the severity of hearing thresholds.
She earned her undergraduate degree in Speech and Hearing Science from The George Washington University in 2002.
In this review, we discuss the roles the Mycs play in the body and what led us to choose them to be our candidate gene for inner ear therapies. The basilar membrane is the support for the organ of Corti supporting cells and hair cells. As the fluid waves propagate through the scalae, they cause vibrations of the overlaying basilar membrane. Depending on the degree of hair cell loss, hearing aids may have limited benefit as no increase in amplitude is able to stimulate lost hair cells (Figure 1E).
Once hair cells are lost, manipulation of inner ear supporting cells may be possible to form new hair cells. The Complex Balance of Proliferation and Differentiation Is Not Well Understood in the Mammalian Inner EarThe balance of proliferation and differentiation is life-long and necessary for the proper development and function of specialized cells [55,67,68,69]. Upon viewing a longitudinal cross section, the cochlear canal is divided into three compartments (scalae). Prolonged exposure to high intensity sound poses high risk for auditory function and can lower hearing thresholds. High tone loss refers to reduced sensitivity of high frequency acoustic stimulus, as opposed to low tone loss for the low frequencies. We will summarize the recently published work describing the early and late effects of N-Myc and L-Myc on hair cell formation and maintenance.
Combined, they physically and ionically separate the scala tympani and the endolymphatic fluid-filled scala media.
This vibration results in a shearing force of organ of Corti hair cells against the tectorial membrane to activate the auditory nerve (A).
Furthermore, because hearing aids mostly increase indiscriminately the amplitude to the ear, this may create additional damage to the remaining hair cells or otherwise cause patient discomfort. On the other hand, an alternative source of cells, such as stem cells could be first manipulated to form hair cell-like cells and then targeted to the damaged tissue to restore hearing. Ear Development Is a Controlled Balance of Proliferation and DifferentiationThe development of the inner ear is dependent upon the robust regulation of proliferation and differentiation that transforms a small patch of undifferentiated ectodermal cells adjacent to the hindbrain into a complex, three-dimensional, functional labyrinth that perceives a wide frequency of sound and participates in multisystem integration to coordinate balance. At a certain point, tumor suppressor genes, pro-sensory genes, and pro-neural genes increase leading to the asymmetric division of NS precursor cells into differentiated NS cells. Understanding the mechanisms behind this balance is an essential question to developmental biology, cancer biology, and regenerative medicine as this balance defines the development of any organism when adequately regulated but leads to cancer when deregulated and leads to regeneration when properly manipulated. The scala media filled with endolymph, lies between two larger perilymphatic filled compartments, the scala vestibuli and scala tympani. The terms profound, mild and moderate describe the descending order of different severity levels of hearing impairments. She also gained additional experience working with children with special needs including children with autism spectrum disorder, cerebral palsy, Down syndrome, and auditory processing disorders when she was employed at the former Spectrum Center in Bethesda, MD. Lastly, we detail the translational significance of our findings and what future work must be performed to make the ultimate hearing aid: the regeneration of the organ of Corti. Vibrations of the basilar membrane move organ of Corti hair cells against the tectorial membrane to provide a shearing force. Some modern hearing aids can be digitally programmed to provide somewhat discriminated amplification avoiding to an extent this problem.
Concomitant and interdependent with proliferation and subsequent differentiation are otic placode induction, organ of Corti specification, and neurosensory cell formation and maintenance.


The formation of NS cells such as neurons and hair cells help maintain the differentiated state of nearby supporting cells.
In some tissues, this balance is easily shifted, such that in response to injury, cells are able to re-initiate the cell cycle to produce new cells and functionally replace the damaged tissue. Among environmental factors, different viral infections, as well as neonatal anoxia and hyperbilirubinemia, can also cause permanent hearing defects.
When hearing loss is the only apparent abnormality, it is referred to as non-syndromic hearing loss (NSHL). The shearing force results in opening of ion channels at the tips of stereocilia and depolarization of hair cells.
Other hearing prostheses such as the bone anchored hearing aid (BAHA) [10,11] or direct acoustic cochlear stimulation (DACS) [12] are often insufficient. The differentiated state is further maintained by high levels of cyclin dependent kinase inhibitors (CDKIs) and retinoblastoma (Rb). The mammalian inner ear is on the far side of this balance and once cells become post-mitotic they are unable to re-enter the cell cycle naturally, perhaps due to the complexity of the inner ear, which allows for robust hearing that may be disrupted if proliferation were re-initiated.Therapies towards regeneration of the complex hearing organ demand an understanding of how the balance shifts from a mitotically active to a post-mitotic state with subsequent cellular differentiation during normal development.
Red indicates pathways favoring differentiation, blue indicates pathways favoring proliferation.
Long term augmentation of ototoxic drugs such as aminoglycoside and gentamicin antibiotics has an adverse effect on the auditory system and accounts for hearing defects. Depolarization mediated transmitter release ultimately generates depolarizations on neurosensory afferents that send neural impulses through the spiral ganglion neurons to the cochlear nucleus of the brainstem and eventually to the auditory cortex, allowing those initial sound waves to be interpreted as meaningful stimuli (Figure 1A).
The best of the current treatments for patients with neurosensory hearing loss are cochlear implants, a prosthesis that is surgically inserted into the scala tympani of the inner ear and stimulates nearby spiral ganglion neuron processes (Figure 1F). There may be an intricate interconnectedness in both space and time between key pro-proliferation factors (N-Myc and L-Myc) and pro-differentiation factors (Neurod1 and Atoh1) in the ear [55], such that disruption in proliferation disrupts proper differentiation. Unlike the genetics factors dictated by hereditary information, some of the environmental factors can be reduced and avoided by raising awareness for appropriate protection.
Hearing loss occurs when sound waves from the environment are unable to sufficiently stimulate the organ of Corti hair cells to send neural impulses to the brain (conductive hearing loss) or if hair cells are lost (sensorineural hearing loss).Conductive and sensorineural hearing losses (SNHL) both affect the stimulation of organ of Corti hair cells, but in different ways.
In conductive hearing loss (B), sound waves are not accurately propagated to the inner ear.
This is supported by various interactome networks elsewhere in the body [70] which have shown that dynamic modular structures regulate the balance of proliferation and differentiation [68].Proliferation is modulated by redundant cell cycle checkpoints.
In cases of conductive hearing loss, sound waves are hindered from reaching the hair cells, often through increased resistance in the middle ear, as is the case in otosclerosis or otitis media (Figure 1B). The normal organ of Corti has over 15,000 hair cells that are organized into one row of inner hair cells plus three rows of outer hair cells aligned along the two-and-a-half turn cochlea such that a single set of hair cells responds to a narrow frequency range enabling high frequency sound resolution from 2–20 kHz in humans, and up to 61 kHz in mouse [13]. Because of the resulting decreased amplitude of sound waves reaching the inner ear, conductive hearing loss can be partially overcome with either hearing aids, an auditory prosthesis in which sound waves are amplified prior to entering the ear canal (Figure 1C), or surgery, to mitigate the impedance. In patients with cochlear implants, only a small set (as little as 6–8) of electrodes are used to recapitulate the 15,000 hair cells and although individual performance does improve over time, patients suffer under many listener environments, are never able to fully appreciate various tones [14,15,16,17,18], and their hearing age never reaches their chronological age; however, the younger the patient, the better the outcome [19,20]. Hearing aids (E) can partially overcome the resulting hearing deficit by increasing the amplitude to nearby cells; however, no hearing aid can stimulate lost hair cells and furthermore, hearing aids may create discomfort by over-stimulating remaining hair cells. Furthermore, without proper neurotrophic factors provided by hair cells to the neurons, neurons may be progressively lost, as they are in animal models [21,22], but limited human data indicate otherwise [23].
Additionally, each cell cycle checkpoint has a unique function and a unique set of associated factors. In SNHL, sound waves enter the ear canal and are transformed into physical vibrations of normal amplitude; however, damaged hair cells are unable to respond to the vibrations and fail to stimulate ganglion neurons (Figure 1D). The best current treatment for sensorineural hearing loss is cochlear implants (F) which directly stimulate auditory neurons through an electrode array surgically implanted into the inner ear.
This makes research into long-term neuronal survival crucial for continued success of cochlear implants [24].
Together, current prostheses are unable to provide a long-term solution capable of perfect hearing restoration, relegating the “world’s best hearing aid” to regeneration of the damaged or lost organ of Corti [25]. Myc does not homodimerize under normal conditions and rarely binds sequence specific DNA in isolation [104].
Inherited hearing loss occurs when genes necessary for normal hair cell formation are mutated, resulting in either developmental malformations of the organ of Corti hair cells or predisposition to hair cell damage.
Myc heterodimerizes with Myc Associated factor X (Max) and binds to DNA with its C-terminal domain and regulates transcription with is N-terminal domain [105]. Organ of Corti SpecificationThe molecular cascade that begins the induction and invagination processes that result in the formation of the otic vesicle are essential to the identity of the organ of Corti. When pRb is phosphorylated, the E2Fs are freed to bind to the promoter region of S-phase promoting genes and the cell continues into S-phase. Myc competes with antagonists Mnt, Mxd, Mga, and the rest of the Mad family, which are highly expressed in differentiated cells, [106,107,108] for binding to Max.
Ultimately, inherited hearing loss must be treated as early as possible with personalized treatment to ensure near-normal, lifelong communication and language development [8,9]. Bmp4, the Fgfs, Shh, and the Wnts specify the boundaries of and make a “topological blueprint” for the forming organ of Corti [58,59]. Both sets of heterodimers bind the same target genes [109]; however, the accessory binding proteins differ [110].
Prevention of Hearing Loss as a First-Line TreatmentThere are two avenues that may ultimately prove to be of help for hearing loss: first, prevention of hair cell loss, and secondly, regeneration of damaged or lost hair cells.
These genes transform the neuroectodermal cells of the otic vesicle into competent, yet still proliferating, neurosensory precursor cells [55]. Here, a number of upstream growth factors modulate levels of cyclinD and cyclinE as well as cdk2, cdk4, and cdk6.
Thus, proto-oncogenes and tumor suppressors are embedded in a complicated network which integrates a number of mitogenic signals forming feedback loops to control the level of mitotic activity in the cell. Currently, certain acquired hair cell losses are mostly unpreventable (cisplatin treatment, for example); but, prevention may one day be possible through increasing the resilience of hair cells’ natural maintenance mechanisms. In the ear, the cell cycle dynamics are likely similar as elsewhere in the body but the full mechanisms have yet-to-be worked out. Atoh1 is known to be necessary for hair cell formation [26] and in the absence of Atoh1 [27], with only transient expression of Atoh1 [28], or in the absence of Atoh1 downstream genes Pou4f3 [2,29,30] and Barhl1 [31], hair cells are lost.
Manipulation of these or other yet-to-be determined genes may prove to be sufficient to prevent organ of Corti hair cell death and subsequent hearing loss. Additionally, other avenues to prevent hair cell death through manipulation of reactive oxygen species, which may play a role in cisplatin treatment for example, are being explored [32]. For example, null mice lacking p27Kip1 contain cells that are able to stay in the cell cycle longer than control cells, generating supernumerary hair cells; however, these cells are not functional and die [77,78]. Likewise, overexpression of cyclinD1 in supporting cells is able to induce transient cell cycle re-entry [79], but cell cycle re-entry had poor yield.While direct alteration of the phosphorylation state of pRb is one method to manipulate cell cycle dynamics, manipulations of mitogenic signaling at the cell surface has also been performed [80,81,82,83]. Regeneration of Hair Cells when Prevention FailsIn cases where hair cell loss is not prevented, hair cell regeneration may be the avenue of choice and would likely be achieved through targeted proliferation followed by the directed differentiation of either stem cells or inner ear cells, such as supporting cells [33,34].
The Fgfs, Tgf-?, Shh, and Wnts, many of the genes necessary for the early induction and identity of the inner ear, play later roles in patterning and proliferation of the ear. In non-mammalian species, damage to hair cells is swiftly responded to through re-initiation of proliferation of supporting cells [35,36,37,38,39]. Manipulations of these ligands and receptors resulted in vestibular cell cycle re-entry in early stages of development but this capacity was lost at later ages [84], suggesting regulation at this level is likely not sufficient for late or long-term cell cycle re-entry.
In summary, despite the known importance of proliferation and differentiation, the complex network of the inner ear cell cycle remains mostly enigmatic, yet it represents a source of great therapeutic potential for hair cell regeneration that requires further exploration.
Either, cell cycle re-entry of the supporting cell dedifferentiates the supporting cell to form a neurosensory precursor cell which then undergoes cellular division to form two cells with subsequent differentiation into one hair cell and one supporting cell. Or, the cell cycle re-entry of the supporting cell forms two supporting cells (with no dedifferentiation) with one of the supporting cells transdifferentiating into a hair cell. Transdifferentiation is the process of directly transforming from one differentiated cell type into a unique second differentiated cell type and has been shown to be possible using various molecular means [40,41,42]. The Mycs Are an Important Node Integrating Proliferation with Cellular DifferentiationDue to the cell death seen with manipulations of downstream genes and lack of late forced cell cycle re-entry with upstream pathways, we aimed to target a node that not only incorporated the upstream pathways and synergized them into the downstream pathway, but one that could also interact with cellular differentiation.
Regardless, since mammalian inner ear cells are unable to re-enter the cell cycle, transforming supporting cells into hair cells would lead to a depletion of supporting cells.
As previously stated, bHLH TFs are needed for the differentiation of sensory neurons and organ of Corti hair cells. Since transformed supporting cells cannot sustain newly formed hair cells, proliferation is required for mammalian hair cell regeneration to provide enough cellular material for both supporting cell and hair cell differentiation. Some bHLH TFs antagonize cellular proliferation and induce differentiation [85,86,87], indicating that bHLH TFs are able to simultaneously manipulate both pathways. Unfortunately, current attempts at forced cell cycle re-entry of differentiated cells results in cells have limited viability [43,44,45,46].Aside from the use of supporting cells, pluri- or multipotent stem cells could be used as a source of precursor populations [33,34]. Transforming a stem cell into a hair cell-like cell requires recapitulating the normal developmental process from naive ectoderm to neurosensory precursor to differentiated hair cell [47], with the first several steps performed in vitro prior to seeding the damaged cochlea. Contextual clues remaining in the cochlea may be sufficient for final placement and differentiation of the neurosensory precursors; however, only a few markers that originally define the organ of Corti and differentiate hair cells remain later in life [27,48] and may not prove sufficient for hair cell placement and differentiation.
Indeed, recent data on the use of Atoh1 misexpression support the conclusion already reached in earlier work, namely that hair cell formation can be initiated but the hair cell may not be long-term viable and certainly cannot be induced after a certain stage in postnatal development [49].
In addition, both under- and overexpression of Atoh1 can result in hair cell death [28,50].
In summary, regeneration avenues using forced cell cycle re-entry or stem cell manipulation are only feasible if proliferation in the inner ear is understood to the level needed to manipulate these two pathways successfully (Figure 2).



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