Keynote review: The auditory system, hearing loss and potential targets for drug development.

There is a huge potential market for the treatment of hearing loss. Drugs are already available to ameliorate predictable, damaging effects of excessive noise and ototoxic drugs. The biggest challenge now is to develop drug-based treatments for regeneration of sensory cells following noise-induced and age-related hearing loss. This requires careful consideration of the physiological mechanisms of hearing loss and identification of key cellular and molecular targets. There are many molecular cues for the discovery of suitable drug targets and a full range of experimental resources are available for initial screening through to functional analysis in vivo. There is now an unparalleled opportunity for translational research.

[1]  David J. Anderson,et al.  neurogenin1 Is Essential for the Determination of Neuronal Precursors for Proximal Cranial Sensory Ganglia , 1998, Neuron.

[2]  J. T. Corwin,et al.  Brief Treatments with Forskolin Enhance S-Phase Entry in Balance Epithelia from the Ears of Rats , 2001, The Journal of Neuroscience.

[3]  Susan J Allen,et al.  Molecular characterization of conditionally immortalized cell lines derived from mouse early embryonic inner ear , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[4]  M. Charles Liberman,et al.  Prestin is required for electromotility of the outer hair cell and for the cochlear amplifier , 2002, Nature.

[5]  J. Nadol,et al.  Patterns of neural degeneration in the human cochlea and auditory nerve: implications for cochlear implantation. , 1997, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[6]  M. Bogoyevitch Therapeutic promise of JNK ATP-noncompetitive inhibitors. , 2005, Trends in molecular medicine.

[7]  The genetics of deafness. , 2003 .

[8]  J. T. Corwin,et al.  Intracellular Signals That Control Cell Proliferation in Mammalian Balance Epithelia: Key Roles for Phosphatidylinositol-3 Kinase, Mammalian Target of Rapamycin, and S6 Kinases in Preference to Calcium, Protein Kinase C, and Mitogen-Activated Protein Kinase , 2001, The Journal of Neuroscience.

[9]  M. Ulfendahl,et al.  NGF stimulates extensive neurite outgrowth from implanted dorsal root ganglion neurons following transplantation into the adult rat inner ear , 2005, Neurobiology of Disease.

[10]  Hirofumi Nakatomi,et al.  Regeneration of Hippocampal Pyramidal Neurons after Ischemic Brain Injury by Recruitment of Endogenous Neural Progenitors , 2002, Cell.

[11]  R. Hertzano,et al.  Brn-3c (POU4F3) regulates BDNF and NT-3 promoter activity. , 2004, Biochemical and biophysical research communications.

[12]  E. Rubel,et al.  Delta1 expression during avian hair cell regeneration. , 1999, Development.

[13]  R. Davis Gradients of Neurotrophins, Ion Channels, and Tuning in the Cochlea , 2003, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[14]  C. Kros,et al.  Differentiation of Mammalian Vestibular Hair Cells from Conditionally Immortal, Postnatal Supporting Cells , 1999, The Journal of Neuroscience.

[15]  K. Ohlemiller,et al.  Apical‐to‐basal gradients in age‐related cochlear degeneration and their relationship to “primary” loss of cochlear neurons , 2004, The Journal of comparative neurology.

[16]  M. Torres,et al.  The development of the vertebrate inner ear , 1998, Mechanisms of Development.

[17]  P. Mburu,et al.  Models of congenital deafness: Mouse and zebrafish , 2005 .

[18]  J. T. Corwin,et al.  The developing organ of Corti contains retinoic acid and forms supernumerary hair cells in response to exogenous retinoic acid in culture. , 1993, Development.

[19]  Huawei Li,et al.  Stem cells as therapy for hearing loss. , 2004, Trends in molecular medicine.

[20]  Manfred Kössl,et al.  A Targeted Deletion in α-Tectorin Reveals that the Tectorial Membrane Is Required for the Gain and Timing of Cochlear Feedback , 2000, Neuron.

[21]  U. Pirvola,et al.  Neurotrophic factors during inner ear development. , 2003, Current topics in developmental biology.

[22]  F. Doetsch,et al.  A niche for adult neural stem cells. , 2003, Current opinion in genetics & development.

[23]  L. Gillespie,et al.  Role Of Trophic Factors In The Development, Survival And Repair Of Primary Auditory Neurons , 2002, Clinical and experimental pharmacology & physiology.

[24]  Bernd Fritzsch,et al.  Auditory system development: primary auditory neurons and their targets. , 2002, Annual review of neuroscience.

[25]  C. Brumwell,et al.  Role for Basic Fibroblast Growth Factor (FGF-2) in Tyrosine Kinase (TrkB) Expression in the Early Development and Innervation of the Auditory Receptor: In Vitro and in Situ Studies , 2000, Experimental Neurology.

[26]  B. Delprat,et al.  Deafness and Cochlear Fibrocyte Alterations in Mice Deficient for the Inner Ear Protein Otospiralin , 2005, Molecular and Cellular Biology.

[27]  Joe C. Adams,et al.  Changes in Cytochemistry of Sensory and Nonsensory Cells in Gentamicin-Treated Cochleas , 2003, Journal of the Association for Research in Otolaryngology.

[28]  D. K. Morest,et al.  Fibroblast growth factors (FGF‐1, FGF‐2) promote migration and neurite growth of mouse cochlear ganglion cells in vitro: Immunohistochemistry and antibody perturbation , 2000, Journal of neuroscience research.

[29]  S. Mcconnell,et al.  FGFR1 Is Required for the Development of the Auditory Sensory Epithelium , 2002, Neuron.

[30]  A. Forge Outer hair cell loss and supporting cell expansion following chronic gentamicin treatment , 1985, Hearing Research.

[31]  J. Corwin,et al.  Regeneration of sensory cells after laser ablation in the lateral line system: hair cell lineage and macrophage behavior revealed by time- lapse video microscopy , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[32]  A. Egner,et al.  Hair cell synaptic ribbons are essential for synchronous auditory signalling , 2005, Nature.

[33]  A. Forge,et al.  Hair cell regeneration in sensory epithelia from the inner ear of a urodele amphibian , 2005, The Journal of comparative neurology.

[34]  E. Rubel,et al.  Cell division in the gerbil cochlea after acoustic trauma. , 1994, The American journal of otology.

[35]  W. Gao,et al.  Overexpression of Math1 induces robust production of extra hair cells in postnatal rat inner ears , 2000, Nature Neuroscience.

[36]  K. Kawamoto,et al.  Math1 Gene Transfer Generates New Cochlear Hair Cells in Mature Guinea Pigs In Vivo , 2003, The Journal of Neuroscience.

[37]  R. D'Agostino,et al.  The relation of hearing in the elderly to the presence of cardiovascular disease and cardiovascular risk factors. , 1993, Archives of otolaryngology--head & neck surgery.

[38]  K. Ohlemiller Age-related hearing loss: the status of Schuknecht’s typology , 2004, Current opinion in otolaryngology & head and neck surgery.

[39]  C. Swanton Cell-cycle targeted therapies. , 2004, The Lancet. Oncology.

[40]  Bechara Kachar,et al.  Establishment and characterization of conditionally immortalized organ of corti cell lines , 1999, Cell biology international.

[41]  R. Ramsden,et al.  Cochlear implants and brain stem implants. , 2002, British medical bulletin.

[42]  C. Avendaño,et al.  Delayed Inner Ear Maturation and Neuronal Loss in PostnatalIgf-1-Deficient Mice , 2001, The Journal of Neuroscience.

[43]  J. Frisén,et al.  Survival and neural differentiation of adult neural stem cells transplanted into the mature inner ear. , 2005, Experimental cell research.

[44]  Jos J Eggermont,et al.  Tinnitus: neurobiological substrates. , 2005, Drug discovery today.

[45]  M. Holley,et al.  GATA3 and NeuroD distinguish auditory and vestibular neurons during development of the mammalian inner ear , 2004, Mechanisms of Development.

[46]  Heidi L. Rehm,et al.  TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells , 2004, Nature.

[47]  R. Debs,et al.  Id genes and proteins as promising targets in cancer therapy. , 2004, Trends in molecular medicine.

[48]  Bernd Fritzsch,et al.  The retinoblastoma gene pathway regulates the postmitotic state of hair cells of the mouse inner ear , 2005, Development.

[49]  J. T. Corwin,et al.  Post-translational protein modification as the substrate for long-lasting memory , 2005 .

[50]  R. Elkon,et al.  Transcription profiling of inner ears from Pou4f3(ddl/ddl) identifies Gfi1 as a target of the Pou4f3 deafness gene. , 2004, Human molecular genetics.

[51]  E. Rubel,et al.  Cellular studies of auditory hair cell regeneration in birds. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[52]  J. Ito,et al.  Trophic support of mouse inner ear by neural stem cell transplantation , 2003, Neuroreport.

[53]  G. Camarero,et al.  Trophic effects of insulin-like growth factor-I (IGF-I) in the inner ear , 2004, Hearing Research.

[54]  R. Hata,et al.  Adenovirus-mediated overexpression of a gene prevents hearing loss and progressive inner hair cell loss after transient cochlear ischemia in gerbils , 2003, Gene Therapy.

[55]  C. Babbs,et al.  Identification and analysis of genes from the mouse otic vesicle and their association with developmental subprocesses through in situ hybridization. , 2004, Developmental biology.

[56]  W. Gao,et al.  Robust generation of new hair cells in the mature mammalian inner ear by adenoviral expression of Hath1 , 2003, Molecular and Cellular Neuroscience.

[57]  R. Pujol,et al.  Characterization of atypical cells in the juvenile rat organ of corti after aminoglycoside ototoxicity , 1998, The Journal of comparative neurology.

[58]  Y. Raphael,et al.  Scar formation after drug-induced cochlear insult , 1991, Hearing Research.

[59]  Bassem A. Hassan,et al.  Math1: an essential gene for the generation of inner ear hair cells. , 1999, Science.

[60]  D. Fashena,et al.  Hair cell recovery in mitotically blocked cultures of the bullfrog saccule. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[61]  L. Rybak,et al.  Ototoxicity: therapeutic opportunities. , 2005, Drug discovery today.

[62]  Michael G. Rosenfeld,et al.  Role of transcription factors a Brn-3.1 and Brn-3.2 in auditory and visual system development , 1996, Nature.

[63]  R. Fettiplace,et al.  Force generation by mammalian hair bundles supports a role in cochlear amplification , 2005, Nature.

[64]  Ryosei Minoda,et al.  Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals , 2005, Nature Medicine.

[65]  Huawei Li,et al.  Pluripotent stem cells from the adult mouse inner ear , 2003, Nature Medicine.

[66]  C. A. Gardner,et al.  Immortalized cell lines from embryonic avian and murine otocysts: Tools for molecular studies of the developing inner ear , 1997, International Journal of Developmental Neuroscience.

[67]  Doris K. Wu,et al.  Revisiting cell fate specification in the inner ear , 2002, Current Opinion in Neurobiology.

[68]  Jean-Luc Puel,et al.  The inner hair cell afferent/efferent synapses revisited: a basis for new therapeutic strategies. , 2002, Advances in oto-rhino-laryngology.

[69]  R. Kageyama,et al.  Fate of neural stem cells grafted into injured inner ears of mice , 2003, Neuroreport.

[70]  H. Zoghbi,et al.  The role of Math1 in inner ear development: Uncoupling the establishment of the sensory primordium from hair cell fate determination. , 2002, Development.

[71]  Rudolf Jaenisch,et al.  Complementary roles of BDNF and NT-3 in vestibular and auditory development , 1995, Neuron.

[72]  Bernd Fritzsch,et al.  Neurotrophins in the ear: their roles in sensory neuron survival and fiber guidance. , 2004, Progress in brain research.

[73]  M. Guitton,et al.  Calpain activity in the amikacin‐damaged rat cochlea , 2004, The Journal of comparative neurology.

[74]  U. Wolfrum,et al.  Interactions in the network of Usher syndrome type 1 proteins. , 2005, Human molecular genetics.

[75]  Huawei Li,et al.  Islet‐1 expression in the developing chicken inner ear , 2004, The Journal of comparative neurology.

[76]  A. Zine Molecular mechanisms that regulate auditory hair-cell differentiation in the mammalian cochlea , 2003, Molecular Neurobiology.

[77]  W. Gao,et al.  Induction of Cell Proliferation by Fibroblast and Insulin-Like Growth Factors in Pure Rat Inner Ear Epithelial Cell Cultures , 1997, The Journal of Neuroscience.

[78]  A. Forge,et al.  The molecular architecture of the inner ear. , 2002, British medical bulletin.

[79]  E. Rubel,et al.  Hair cell regeneration: winging our way towards a sound future , 2003, Current Opinion in Neurobiology.

[80]  M. Seidman,et al.  Intratympanic treatment of hearing loss with novel and traditional agents. , 2004, Otolaryngologic clinics of North America.

[81]  E. Oesterle,et al.  Transforming growth factor α with insulin stimulates cell proliferation in vivo in adult rat vestibular sensory epithelium , 1998, The Journal of comparative neurology.

[82]  B. Casado,et al.  Proteomics: A Primer for Otologists , 2004, Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology.

[83]  K. Fujino,et al.  Transplantation of neural stem cells into explants of Rat inner ear , 2004, Acta oto-laryngologica. Supplementum.

[84]  J. R. Holt,et al.  Auditory amplification: outer hair cells pres the issue , 2003, Trends in Neurosciences.

[85]  T. Hasson,et al.  Requirement for Brn-3c in maturation and survival, but not in fate determination of inner ear hair cells. , 1998, Development.

[86]  M. A. Reid,et al.  Opposite Actions of Brain-Derived Neurotrophic Factor and Neurotrophin-3 on Firing Features and Ion Channel Composition of Murine Spiral Ganglion Neurons , 2002, The Journal of Neuroscience.

[87]  J. T. Corwin,et al.  Regeneration in avian hair cell epithelia: identification of intracellular signals required for S‐phase entry , 2001, The European journal of neuroscience.

[88]  F. Grosveld,et al.  Transcription factor GATA‐3 alters pathway selection of olivocochlear neurons and affects morphogenesis of the ear , 2001, The Journal of comparative neurology.

[89]  Wei Liu,et al.  Spontaneous hair-cell renewal following gentamicin exposure in postnatal rat utricular explants , 2003, Hearing Research.

[90]  D. Lim,et al.  A Cochlear Cell Line as an in vitro System for Drug Ototoxicity Screening , 2003, Audiology and Neurotology.

[91]  D. Baguley,et al.  Mechanisms of tinnitus. , 2002, British medical bulletin.

[92]  W. Bloch,et al.  In vitro activation of extracellular signal-regulated kinase1/2 in the inner ear of guinea pigs , 2002, Brain Research.

[93]  Y. Dobashi,et al.  Perspectives on cancer therapy: cell cycle blockers and perturbators. , 2003, Current medicinal chemistry.

[94]  R. Ruben Redefining the Survival of the Fittest: Communication Disorders in the 21st Century , 2000, The Laryngoscope.

[95]  Bernd Fritzsch,et al.  NT-3 Replacement with Brain-Derived Neurotrophic Factor Redirects Vestibular Nerve Fibers to the Cochlea , 2004, The Journal of Neuroscience.

[96]  M. Holley,et al.  Cell lines in inner ear research. , 2002, Journal of neurobiology.

[97]  D. Fekete Development of the vertebrate ear: insights from knockouts and mutants , 1999, Trends in Neurosciences.

[98]  D. van der Kooy,et al.  Retinal stem cells in the adult mammalian eye. , 2000, Science.

[99]  M. Montcouquiol,et al.  Math1 regulates development of the sensory epithelium in the mammalian cochlea , 2004, Nature Neuroscience.

[100]  R. Ruben Development of the inner ear of the mouse: a radioautographic study of terminal mitoses. , 1967, Acta oto-laryngologica.

[101]  M. Gurney,et al.  SEL-10 Is an Inhibitor of Notch Signaling That Targets Notch for Ubiquitin-Mediated Protein Degradation , 2001, Molecular and Cellular Biology.

[102]  Tatsuo Nakamura,et al.  Transplantation of bone marrow stromal cells into the cochlea of chinchillas , 2004, Neuroreport.

[103]  Chang Liu,et al.  Apoptosis and hair cell degeneration in the vestibular sensory epithelia of the guinea pig following a gentamicin insult , 1997, Hearing Research.

[104]  M. Salminen,et al.  Xenografted fetal dorsal root ganglion, embryonic stem cell and adult neural stem cell survival following implantation into the adult vestibulocochlear nerve , 2005, Experimental Neurology.

[105]  James M. Roberts,et al.  Gene disruption of p27(Kip1) allows cell proliferation in the postnatal and adult organ of corti. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[106]  Peter J Schultheiss,et al.  Growth factor treatment enhances vestibular hair cell renewal and results in improved vestibular function , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[107]  D. Fekete,et al.  Hair Cells and Supporting Cells Share a Common Progenitor in the Avian Inner Ear , 1998, The Journal of Neuroscience.

[108]  M. Milo,et al.  Ventral otic cell lines as developmental models of auditory epithelial and neural precursors , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[109]  F. de Ribaupierre,et al.  A Peptide Inhibitor of C-jun N-terminal Kinase Protects against Both Aminoglycoside and Acoustic Trauma-induced Auditory Hair Cell Death and Hearing Loss , 2022 .

[110]  J. Brockes,et al.  Mammalian postmitotic nuclei reenter the cell cycle after serum stimulation in newt/mouse hybrid myotubes , 2001, Current Biology.

[111]  J. T. Corwin,et al.  An RT-PCR analysis of mRNA for growth factor receptors in damaged and control sensory epithelia of rat utricles , 1996, Hearing Research.

[112]  W. Brownell,et al.  Essential role of BETA2/NeuroD1 in development of the vestibular and auditory systems. , 2000, Genes & development.

[113]  Andrew Forge,et al.  Mutations in the gene for connexin 26 (GJB2) that cause hearing loss have a dominant negative effect on connexin 30. , 2003, Human molecular genetics.

[114]  R. Humphries,et al.  Correlation of Murine Embryonic Stem Cell Gene Expression Profiles with Functional Measures of Pluripotency , 2005, Stem cells.

[115]  R. Salvi,et al.  Time course of efferent fiber and spiral ganglion cell degeneration following complete hair cell loss in the chinchilla , 2004, Brain Research.

[116]  D. Cotanche,et al.  Potential role of BFGF and retinoic acid in the regeneration of chicken cochlear hair cells , 1996, Hearing Research.

[117]  D. Cotanche,et al.  Regeneration of the inner ear as a model of neural plasticity , 2004, Journal of neuroscience research.

[118]  M. Lovett,et al.  Gene expression differences in quiescent versus regenerating hair cells of avian sensory epithelia: implications for human hearing and balance disorders. , 2003, Human molecular genetics.

[119]  E. Lynch,et al.  Compounds for the prevention and treatment of noise-induced hearing loss. , 2005, Drug discovery today.

[120]  L. Miele,et al.  Toward the rational design of cell fate modifiers: notch signaling as a target for novel biopharmaceuticals. , 2000, Current pharmaceutical biotechnology.

[121]  A. Forge,et al.  Morphological evidence for supporting cell to hair cell conversion in the mammalian utricular macula , 1997, International Journal of Developmental Neuroscience.

[122]  David J. Anderson,et al.  Neurogenin 1 Null Mutant Ears Develop Fewer, Morphologically Normal Hair Cells in Smaller Sensory Epithelia Devoid of Innervation , 2000, Journal of the Association for Research in Otolaryngology.

[123]  Sonja Nowotschin,et al.  Suppression of neural fate and control of inner ear morphogenesis by Tbx1 , 2004, Development.

[124]  W. Gao,et al.  Establishment of conditionally immortalized rat utricular epithelial cell lines using a retrovirus-mediated gene transfer technique , 1998, Hearing Research.

[125]  R. D'Agostino,et al.  Effects of age on the distortion product otoacoustic emission growth functions , 2002, Hearing Research.

[126]  M. Kelley Cell adhesion molecules during inner ear and hair cell development, including notch and its ligands. , 2003, Current topics in developmental biology.

[127]  Y. Sasai,et al.  Fates of mouse embryonic stem cells transplanted into the inner ears of adult mice and embryonic chickens. , 2004, Acta oto-laryngologica. Supplementum.

[128]  Wei Pan,et al.  Identification of gene expression profiles in rat ears with cDNA microarrays , 2003, Hearing Research.

[129]  S. Leal,et al.  Mutations in the γ-Actin Gene (ACTG1) Are Associated with Dominant Progressive Deafness (DFNA20/26) , 2003 .

[130]  G. Martin,et al.  Sprouty2, a mouse deafness gene, regulates cell fate decisions in the auditory sensory epithelium by antagonizing FGF signaling. , 2005, Developmental cell.

[131]  Huawei Li,et al.  Generation of hair cells by stepwise differentiation of embryonic stem cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[132]  R Kominami,et al.  Ahl3, a third locus on mouse chromosome 17 affecting age-related hearing loss. , 2004, Biochemical and biophysical research communications.

[133]  Richard R. Fay,et al.  The Mammalian Auditory Pathway: Neuroanatomy , 1992, Springer Handbook of Auditory Research.

[134]  K. Willecke,et al.  Targeted Ablation of Connexin26 in the Inner Ear Epithelial Gap Junction Network Causes Hearing Impairment and Cell Death , 2002, Current Biology.

[135]  Karen P. Steel,et al.  Sox2 is required for sensory organ development in the mammalian inner ear , 2005, Nature.

[136]  M. I. Lomax,et al.  Differential display and gene arrays to examine auditory plasticity , 2000, Hearing Research.

[137]  P. Traxler,et al.  Tyrosine kinases as targets in cancer therapy – successes and failures , 2003, Expert opinion on therapeutic targets.

[138]  Nicolas Daudet,et al.  Two contrasting roles for Notch activity in chick inner ear development: specification of prosensory patches and lateral inhibition of hair-cell differentiation , 2005, Development.

[139]  Mark A. Parker,et al.  The Potential Use of Stem Cells for Cochlear Repair , 2004, Audiology and Neurotology.

[140]  A. Salt,et al.  Local inner-ear drug delivery and pharmacokinetics. , 2005, Drug discovery today.

[141]  J. T. Corwin,et al.  Ultrastructural evidence for hair cell regeneration in the mammalian inner ear. , 1993, Science.

[142]  A. Wise,et al.  Resprouting and survival of guinea pig cochlear neurons in response to the administration of the neurotrophins brain‐derived neurotrophic factor and neurotrophin‐3 , 2005, The Journal of comparative neurology.

[143]  E. Huang,et al.  Brn3a is a transcriptional regulator of soma size, target field innervation and axon pathfinding of inner ear sensory neurons. , 2001, Development.

[144]  Peter Dallos,et al.  Prestin, a new type of motor protein , 2002, Nature Reviews Molecular Cell Biology.

[145]  M. Holley,et al.  Expression of the transcription factors GATA3 and Pax2 during development of the mammalian inner ear , 2002, The Journal of comparative neurology.

[146]  Peter G. Gillespie,et al.  Cadherin 23 is a component of the tip link in hair-cell stereocilia , 2004, Nature.

[147]  J. I. Matsui,et al.  Regeneration and replacement in the vertebrate inner ear. , 2005, Drug discovery today.

[148]  J. T. Corwin,et al.  Regenerative Proliferation in Organ Cultures of the Avian Cochlea: Identification of the Initial Progenitors and Determination of the Latency of the Proliferative Response , 1996, The Journal of Neuroscience.

[149]  H. Zoghbi,et al.  Autoregulation and multiple enhancers control Math1 expression in the developing nervous system. , 2000, Development.

[150]  Peter Dallos,et al.  Prestin and the Dynamic Stiffness of Cochlear Outer Hair Cells , 2003, The Journal of Neuroscience.

[151]  Andrew Forge,et al.  Hair cell recovery in the vestibular sensory epithelia of mature guinea pigs , 1998, The Journal of comparative neurology.

[152]  D. Corey,et al.  Understanding inner ear development with gene expression profiling. , 2002, Journal of neurobiology.

[153]  A. Halsall,et al.  Transcript profiling of functionally related groups of genes during conditional differentiation of a mammalian cochlear hair cell line. , 2002, Genome research.

[154]  D. Lindholm,et al.  Regeneration of human auditory nerve. In vitro/in video demonstration of neural progenitor cells in adult human and guinea pig spiral ganglion , 2005, Hearing Research.

[155]  J. T. Corwin,et al.  Regenerative proliferation in inner ear sensory epithelia from adult guinea pigs and humans. , 1993, Science.

[156]  M. I. Lomax,et al.  Gene Expression Profiles of the Rat Cochlea, Cochlear Nucleus, and Inferior Colliculus , 2002, Journal of the Association for Research in Otolaryngology.

[157]  Rudolf Glueckert,et al.  The Human Spiral Ganglion: New Insights into Ultrastructure, Survival Rate and Implications for Cochlear Implants , 2005, Audiology and Neurotology.

[158]  N. Segil,et al.  p27(Kip1) links cell proliferation to morphogenesis in the developing organ of Corti. , 1999, Development.

[159]  J. Lewis,et al.  Cell fate choices and the expression of Notch, Delta and Serrate homologues in the chick inner ear: parallels with Drosophila sense-organ development. , 1998, Development.

[160]  M. Schwab Repairing the Injured Spinal Cord , 2002, Science.

[161]  C. Petit,et al.  Molecular genetics of hearing loss. , 2001, Annual review of genetics.

[162]  Anders Björklund,et al.  Cell transplantation in Parkinson's disease: how can we make it work? , 2005, Trends in Neurosciences.

[163]  R. Goodyear,et al.  Sensory organ development in the inner ear: molecular and cellular mechanisms. , 2002, British medical bulletin.

[164]  M. Branca Gene therapy: cursed or inching towards credibility? , 2005, Nature Biotechnology.

[165]  K. Steel,et al.  A genetic approach to understanding auditory function , 2001, Nature Genetics.

[166]  Tullio Pozzan,et al.  Impaired permeability to Ins(1,4,5)P3 in a mutant connexin underlies recessive hereditary deafness , 2005, Nature Cell Biology.

[167]  Mitsuru Sugawara,et al.  Survival of Adult Spiral Ganglion Neurons Requires erbB Receptor Signaling in the Inner Ear , 2004, The Journal of Neuroscience.

[168]  Ping Chen,et al.  Progressive hearing loss in mice lacking the cyclin-dependent kinase inhibitor Ink4d , 2003, Nature Cell Biology.

[169]  Julian Lewis,et al.  Forced activation of Wnt signaling alters morphogenesis and sensory organ identity in the chicken inner ear. , 2003, Developmental biology.

[170]  E. Huang,et al.  NeuroD-null mice are deaf due to a severe loss of the inner ear sensory neurons during development. , 2001, Development.

[171]  J. Ito,et al.  Generation of inner ear hair cell immunophenotypes from neurospheres obtained from fetal rat central nervous system in vitro. , 2004, Acta oto-laryngologica. Supplementum.

[172]  I. Thalmann,et al.  Proteomics and the Inner Ear , 2002, Disease markers.

[173]  K. Lyons,et al.  Signaling through BMP type 1 receptors is required for development of interneuron cell types in the dorsal spinal cord , 2004, Development.

[174]  H. Ludman,et al.  Diseases of the Ear , 1910, Glasgow Medical Journal.

[175]  K. Avraham,et al.  Therapeutics of hearing loss: expectations vs reality. , 2005, Drug discovery today.

[176]  M. Charles Liberman,et al.  Spiral Ligament Pathology: A Major Aspect of Age-Related Cochlear Degeneration in C57BL/6 Mice , 2001, Journal of the Association for Research in Otolaryngology.

[177]  J. Ito,et al.  Survival of fetal Rat otocyst cells grafted into the damaged inner ear , 2004, Acta oto-laryngologica. Supplementum.