Review Article
Full Access
The molecular basis of neurosensory cell formation in ear development: a blueprint for hair cell and sensory neuron regeneration?
Bernd Fritzsch,
Kirk W. Beisel,
Laura A. Hansen,
Corresponding Author
Bernd Fritzsch
Creighton University, Department of Biomedical Sciences, Omaha, NE
Creighton University, Department of Biomedical Sciences, Omaha, NE 68178.Search for more papers by this authorKirk W. Beisel
Creighton University, Department of Biomedical Sciences, Omaha, NE
Search for more papers by this authorLaura A. Hansen
Creighton University, Department of Biomedical Sciences, Omaha, NE
Search for more papers by this authorBernd Fritzsch,
Kirk W. Beisel,
Laura A. Hansen,
Corresponding Author
Bernd Fritzsch
Creighton University, Department of Biomedical Sciences, Omaha, NE
Creighton University, Department of Biomedical Sciences, Omaha, NE 68178.Search for more papers by this authorKirk W. Beisel
Creighton University, Department of Biomedical Sciences, Omaha, NE
Search for more papers by this authorLaura A. Hansen
Creighton University, Department of Biomedical Sciences, Omaha, NE
Search for more papers by this authorAbstract
The inner ear of mammals uses neurosensory cells derived from the embryonic ear for mechanoelectric transduction of vestibular and auditory stimuli (the hair cells) and conducts this information to the brain via sensory neurons. As with most other neurons of mammals, lost hair cells and sensory neurons are not spontaneously replaced and result instead in age-dependent progressive hearing loss. We review the molecular basis of neurosensory development in the mouse ear to provide a blueprint for possible enhancement of therapeutically useful transformation of stem cells into lost neurosensory cells. We identify several readily available adult sources of stem cells that express, like the ectoderm-derived ear, genes known to be essential for ear development. Use of these stem cells combined with molecular insights into neurosensory cell specification and proliferation regulation of the ear, might allow for neurosensory regeneration of mammalian ears in the near future. BioEssays 28: 1181–1193, 2006. © 2006 Wiley Periodicals, Inc.
References
- 1 Rakic P. 2006. Neuroscience. No more cortical neurons for you. Science 313: 928–929.
- 2 Rask-Andersen H, Bostrom M, Gerdin B, Kinnefors A, Nyberg G et al. 2005. Regeneration of human auditory nerve. In vitro/in video demonstration of neural progenitor cells in adult human and guinea pig spiral ganglion. Hear Res 203: 180–191.
- 3 Li H, Liu H, Heller S. 2003. Pluripotent stem cells from the adult mouse inner ear. Nat Med 9: 1293–1299.
- 4 Fritzsch B, Tessarollo L, Coppola E, Reichardt LF. 2004. Neurotrophins in the ear: their roles in sensory neuron survival and fiber guidance. Prog Brain Res 146: 265–278.
- 5 Sugawara M, Corfas G, Liberman MC. 2005. Influence of supporting cells on neuronal degeneration after hair cell loss. J Assoc Res Otolaryngol 6: 136–147.
- 6 Roehm PC, Hansen MR. 2005. Strategies to preserve or regenerate spiral ganglion neurons. Curr Opin Otolaryngol Head Neck Surg 13: 294–300.
- 7 Gillespie LN, Shepherd RK. 2005. Clinical application of neurotrophic factors: the potential for primary auditory neuron protection. Eur J Neurosci 22: 2123–2133.
- 8 Staecker H, Brough DE, Praetorius M, Baker K. 2004. Drug delivery to the inner ear using gene therapy. Otolaryngol Clin North Am 37: 1091–1108.
- 9 Chen P, Zindy F, Abdala C, Liu F, Li X, Roussel MF, Segil N. 2003. Progressive hearing loss in mice lacking the cyclin-dependent kinase inhibitor Ink4d. Nat Cell Biol 5: 422–426.
- 10 Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R et al. 2006. Increasing p16(INK4a) expression decreases forebrain progenitors and neurogenesis during ageing. Nature.
- 11 White PM, Doetzlhofer A, Lee YS, Groves AK, Segil N. 2006. Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells. Nature 441: 984–987.
- 12 Kanzaki S, Beyer LA, Swiderski DL, Izumikawa M, Stover T et al. 2006. p27(Kip1) deficiency causes organ of Corti pathology and hearing loss. Hear Res 214: 28–36.
- 13 Mantela J, Jiang Z, Ylikoski J, Fritzsch B, Zacksenhaus E, Pirvola U. 2005. The retinoblastoma gene pathway regulates the postmitotic state of hair cells of the mouse inner ear. Development 132: 2377–2388.
- 14 Sage C, Huang M, Vollrath MA, Brown MC, Hinds PW et al. 2006. Essential role of retinoblastoma protein in mammalian hair cell development and hearing. Proc Natl Acad Sci USA 103: 7345–7350.
- 15 Izumikawa M, Minoda R, Kawamoto K, Abrashkin KA, Swiderski DL et al. 2005. Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nat Med 11: 271–276.
- 16 Colvin JS, Bohne BA, Harding GW, McEwen DG, Ornitz DM. 1996. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet 12: 390–397.
- 17 Rivolta MN, Li H, Heller S. 2006. Generation of inner ear cell types from embryonic stem cells. Methods Mol Biol 330: 71–92.
- 18 Li H, Corrales CE, Edge A, Heller S. 2004. Stem cells as therapy for hearing loss. Trends Mol Med 10: 309–315.
- 19 Rhee H, Polak L, Fuchs E. 2006. Lhx2 maintains stem cell character in hair follicles. Science 312: 1946–1949.
- 20 Kaufman CK, Zhou P, Pasolli HA, Rendl M, Bolotin D et al. 2003. GATA-3: an unexpected regulator of cell lineage determination in skin. Genes Dev 17: 2108–2122.
- 21 Sieber-Blum M, Grim M, Hu YF, Szeder V. 2004. Pluripotent neural crest stem cells in the adult hair follicle. Dev Dyn 231: 258–269.
- 22 Sieber-Blum M, Schnell L, Grim M, Hu YF, Schneider R, Schwab ME. 2006. Characterization of epidermal neural crest stem cell (EPI-NCSC) grafts in the lesioned spinal cord. Mol Cell Neurosci 32: 67–81.
- 23
Groves AK.
The induction of the otic placode. In:
MW Kelley,
DK Wu,
AN Popper,
RR Fay, editors.
Development of the inner ear.
New York:
Springer Verlag;
2005. p
10–42.
10.1007/0-387-30678-1_2 Google Scholar
- 24 Lemaire P, Bertrand V, Hudson C. 2002. Early steps in the formation of neural tissue in ascidian embryos. Dev Biol 252: 151–169.
- 25 Delaune E, Lemaire P, Kodjabachian L. 2005. Neural induction in Xenopus requires early FGF signalling in addition to BMP inhibition. Development 132: 299–310.
- 26 Shou J, Rim PC, Calof AL. 1999. BMPs inhibit neurogenesis by a mechanism involving degradation of a transcription factor. Nat Neurosci 2: 339–345.
- 27 Riccomagno MM, Martinu L, Mulheisen M, Wu DK, Epstein DJ. 2002. Specification of the mammalian cochlea is dependent on Sonic hedgehog. Genes Dev 16: 2365–2378.
- 28 Wright TJ, Hatch EP, Karabagli H, Karabagli P, Schoenwolf GC, Mansour SL. 2003. Expression of mouse fibroblast growth factor and fibroblast growth factor receptor genes during early inner ear development. Dev Dyn 228: 267–272.
- 29 Riccomagno MM, Takada S, Epstein DJ. 2005. Wnt-dependent regulation of inner ear morphogenesis is balanced by the opposing and supporting roles of Shh. Genes Dev 19: 1612–1623.
- 30 Ohyama T, Mohamed OA, Taketo MM, Dufort D, Groves AK. 2006. Wnt signals mediate a fate decision between otic placode and epidermis. Development 133: 865–875.
- 31 Morsli H, Choo D, Ryan A, Johnson R, Wu DK. 1998. Development of the mouse inner ear and origin of its sensory organs. J Neurosci 18: 3327–3335.
- 32 Ma Q, Chen Z, del Barco Barrantes I, de la Pompa JL, Anderson DJ. 1998. neurogenin1 is essential for the determination of neuronal precursors for proximal cranial sensory ganglia. Neuron 20: 469–482.
- 33 Fritzsch B, Beisel KW, Bermingham NA. 2000. Developmental evolutionary biology of the vertebrate ear: conserving mechanoelectric transduction and developmental pathways in diverging morphologies. Neuroreport 11: R35–44.
- 34 Fritzsch B, Beisel KW. 2001. Evolution and development of the vertebrate ear. Brain Res Bull 55: 711–721.
- 35 Caldwell JC, Eberl DF. 2002. Towards a molecular understanding of Drosophila hearing. J Neurobiol 53: 172–189.
- 36 Ghysen A, Dambly-Chaudiere C. 2000. A genetic programme for neuronal connectivity. Trends Genet 16: 221–226.
- 37
Pauley S,
Matei V,
Beisel KW,
Fritzsch B.
Wiring the ear to the brain: the molecular basis of neurosensory development, differentiation, and survival. In:
MK Kelley,
DK Wu,
AN Popper,
RR Fay, editors.
Development of the inner ear.
New York:
Springer Verlag;
2005. p
85–121.
10.1007/0-387-30678-1_4 Google Scholar
- 38 Ma Q, Anderson DJ, Fritzsch B. 2000. Neurogenin 1 null mutant ears develop fewer, morphologically normal hair cells in smaller sensory epithelia devoid of innervation. J Assoc Res Otolaryngol 1: 129–143.
- 39 Matei V, Pauley S, Kaing S, Rowitch D, Beisel KW et al. 2005. Smaller inner ear sensory epithelia in Neurog 1 null mice are related to earlier hair cell cycle exit. Dev Dyn 234: 633–650.
- 40 Ma Q, Kintner C, Anderson DJ. 1996. Identification of neurogenin, a vertebrate neuronal determination gene. Cell 87: 43–52.
- 41 Karis A, Pata I, van Doorninck JH, Grosveld F, de Zeeuw CI et al. 2001. Transcription factor GATA-3 alters pathway selection of olivocochlear neurons and affects morphogenesis of the ear. J Comp Neurol 429: 615–630.
- 42 Torres M, Gomez-Pardo E, Gruss P. 1996. Pax2 contributes to inner ear patterning and optic nerve trajectory. Development 122: 3381–3391.
- 43 Pfeffer PL, Gerster T, Lun K, Brand M, Busslinger M. 1998. Characterization of three novel members of the zebrafish Pax2/5/8 family: dependency of Pax5 and Pax8 expression on the Pax2.1 (noi) function. Development 125: 3063–3074.
- 44 Raft S, Nowotschin S, Liao J, Morrow BE. 2004. Suppression of neural fate and control of inner ear morphogenesis by Tbx1. Development 131: 1801–1812.
- 45
Hatini V,
Ye X,
Balas G,
Lai E.
1999.
Dynamics of placodal lineage development revealed by targeted transgene expression.
Dev Dyn
215:
332–343.
10.1002/(SICI)1097-0177(199908)215:4<332::AID-AJA5>3.0.CO;2-R CAS PubMed Web of Science® Google Scholar
- 46 Pauley S, Lai E, Fritzsch B. 2006. Foxg1 is required for morphogenesis and histogenesis of the mammalian inner ear. Dev Dyn 235: 2470–2482.
- 47 Ohyama T, Groves AK. 2004. Expression of mouse Foxi class genes in early craniofacial development. Dev Dyn 231: 640–646.
- 48 Zou D, Silvius D, Fritzsch B, Xu PX. 2004. Eya1 and Six1 are essential for early steps of sensory neurogenesis in mammalian cranial placodes. Development 131: 5561–5572.
- 49 Reim G, Brand M. 2002. Spiel-ohne-grenzen/pou2 mediates regional competence to respond to Fgf8 during zebrafish early neural development. Development 129: 917–933.
- 50 Massague J, Seoane J, Wotton D. 2005. Smad transcription factors. Genes Dev 19: 2783–2810.
- 51 Blokzijl A, ten Dijke P, Ibanez CF. 2002. Physical and functional interaction between GATA-3 and Smad3 allows TGF-beta regulation of GATA target genes. Curr Biol 12: 35–45.
- 52 Ohuchi H, Yasue A, Ono K, Sasaoka S, Tomonari S et al. 2005. Identification of cis-element regulating expression of the mouse Fgf10 gene during inner ear development. Dev Dyn 233: 177–187.
- 53 Nicolussi A, D'Inzeo S, Santulli M, Colletta G, Coppa A. 2003. TGF-beta control of rat thyroid follicular cells differentiation. Mol Cell Endocrinol 207: 1–11.
- 54 Seoane J, Le HV, Shen L, Anderson SA, Massague J. 2004. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 117: 211–223.
- 55 Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS et al. 2005. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122: 947–956.
- 56 Gowan K, Helms AW, Hunsaker TL, Collisson T, Ebert PJ et al. 2001. Crossinhibitory activities of Ngn1 and Math1 allow specification of distinct dorsal interneurons. Neuron 31: 219–232.
- 57 Zhao Y, Wang Y, Wang Z, Liu H, Shen Y et al. 2006. Sonic hedgehog promotes mouse inner ear progenitor cell proliferation and hair cell generation in vitro. Neuroreport 17: 121–124.
- 58 Mowbray C, Hammerschmidt M, Whitfield TT. 2001. Expression of BMP signalling pathway members in the developing zebrafish inner ear and lateral line. Mech Dev 108: 179–184.
- 59 Farinas I, Jones KR, Tessarollo L, Vigers AJ, Huang E et al. 2001. Spatial shaping of cochlear innervation by temporally regulated neurotrophin expression. J Neurosci 21: 6170–6180.
- 60 Fritzsch B, Beisel KW, Jones K, Farinas I, Maklad A et al. 2002. Development and evolution of inner ear sensory epithelia and their innervation. J Neurobiol 53: 143–156.
- 61 Kiernan AE, Pelling AL, Leung KK, Tang AS, Bell DM et al. 2005. Sox2 is required for sensory organ development in the mammalian inner ear. Nature 434: 1031–1035.
- 62 Radde-Gallwitz K, Pan L, Gan L, Lin X, Segil N, Chen P. 2004. Expression of Islet1 marks the sensory and neuronal lineages in the mammalian inner ear. J Comp Neurol 477: 412–421.
- 63 Pauley S, Wright TJ, Pirvola U, Ornitz D, Beisel K, Fritzsch B. 2003. Expression and function of FGF10 in mammalian inner ear development. Dev Dyn 227: 203–215.
- 64 Kim WY, Fritzsch B, Serls A, Bakel LA, Huang EJ et al. 2001. NeuroD-null mice are deaf due to a severe loss of the inner ear sensory neurons during development. Development 128: 417–426.
- 65 Liu M, Pereira FA, Price SD, Chu MJ, Shope C et al. 2000. Essential role of BETA2/NeuroD1 in development of the vestibular and auditory systems. Genes Dev 14: 2839–2854.
- 66 Fritzsch B, Beisel KW. 2003. Molecular conservation and novelties in vertebrate ear development. Curr Top Dev Biol 57: 1–44.
- 67 Bermingham NA, Hassan BA, Price SD, Vollrath MA, Ben-Arie N et al. 1999. Math1: an essential gene for the generation of inner ear hair cells. Science 284: 1837–1841.
- 68 Fritzsch B, Matei VA, Nichols DH, Bermingham N, Jones K et al. 2005. Atoh1 null mice show directed afferent fiber growth to undifferentiated ear sensory epithelia followed by incomplete fiber retention. Dev Dyn 233: 570–583.
- 69 Satoh T, Fekete DM. 2005. Clonal analysis of the relationships between mechanosensory cells and the neurons that innervate them in the chicken ear. Development 132: 1687–1697.
- 70 Bertrand N, Castro DS, Guillemot F. 2002. Proneural genes and the specification of neural cell types. Nat Rev Neurosci 3: 517–530.
- 71 Calof AL, Bonnin A, Crocker C, Kawauchi S, Murray RC et al. 2002. Progenitor cells of the olfactory receptor neuron lineage. Microsc Res Tech 58: 176–188.
- 72 Beites CL, Kawauchi S, Crocker CE, Calof AL. 2005. Identification and molecular regulation of neural stem cells in the olfactory epithelium. Exp Cell Res 306: 309–316.
- 73 Kawauchi S, Beites CL, Crocker CE, Wu HH, Bonnin A et al. 2004. Molecular signals regulating proliferation of stem and progenitor cells in mouse olfactory epithelium. Dev Neurosci 26: 166–180.
- 74 Kawauchi S, Shou J, Santos R, Hebert JM, McConnell SK et al. 2005. Fgf8 expression defines a morphogenetic center required for olfactory neurogenesis and nasal cavity development in the mouse. Development 132: 5211–5223.
- 75 Wu HH, Ivkovic S, Murray RC, Jaramillo S, Lyons KM et al. 2003. Autoregulation of Neurogenesis by GDF11. Neuron 37: 197–207.
- 76 Lee YS, Liu F, Segil N. 2006. A morphogenetic wave of p27Kip1 transcription directs cell cycle exit during organ of Corti development. Development 133: 2817–2826.
- 77 Jones JM, Montcouquiol M, Dabdoub A, Woods C, Kelley MW. 2006. Inhibitors of differentiation and DNA binding (Ids) regulate Math1 and hair cell formation during the development of the organ of Corti. J Neurosci 26: 550–558.
- 78 Kageyama R, Ohtsuka T, Hatakeyama J, Ohsawa R. 2005. Roles of bHLH genes in neural stem cell differentiation. Exp Cell Res 306: 343–348.
- 79 Pozniak CD, Pleasure SJ. 2006. A tale of two signals: Wnt and Hedgehog in dentate neurogenesis. Sci STKE 2006: pe5.
- 80 Pirvola U, Spencer-Dene B, Xing-Qun L, Kettunen P, Thesleff I et al. 2000. FGF/FGFR-2(IIIb) signaling is essential for inner ear morphogenesis. J Neurosci 20: 6125–6134.
- 81 Wright TJ, Mansour SL. 2003. Fgf3 and Fgf10 are required for mouse otic placode induction. Development 130: 3379–3390.
- 82 Ladher RK, Wright TJ, Moon AM, Mansour SL, Schoenwolf GC. 2005. FGF8 initiates inner ear induction in chick and mouse. Genes Dev 19: 603–613.
- 83 Martynoga B, Morrison H, Price DJ, Mason JO. 2005. Foxg1 is required for specification of ventral telencephalon and region-specific regulation of dorsal telencephalic precursor proliferation and apoptosis. Dev Biol 283: 113–127.
- 84 Yao J, Liu Y, Lo R, Tretjakoff I, Peterson A, Stifani S. 2000. Disrupted development of the cerebral hemispheres in transgenic mice expressing the mammalian Groucho homologue transducin-like-enhancer of split 1 in postmitotic neurons. Mech Dev 93: 105–115.
- 85 Lanford PJ, Kelley MW. Notch signaling and cell fate determination in the vertebrate inner ear. In: MW Kelley, WD K., AN Popper, RR Fay, editors. Development of the Inner Ear. Volume SHAR 26, Springer Handbook of Auditory Research. New York, NY: Springer; 2005. p 122–157.
- 86 Lanford PJ, Lan Y, Jiang R, Lindsell C, Weinmaster G et al. 1999. Notch signalling pathway mediates hair cell development in mammalian cochlea. Nat Genet 21: 289–292.
- 87 Kiernan AE, Xu J, Gridley T. 2006. The Notch Ligand JAG1 Is Required for Sensory Progenitor Development in the Mammalian Inner Ear. PLoS Genet 2: e4.
- 88 Brooker R, Hozumi K, Lewis J. 2006. Notch ligands with contrasting functions: Jagged1 and Delta1 in the mouse inner ear. Development 133: 1277–1286.
- 89 Daudet N, Lewis J. 2005. Two contrasting roles for Notch activity in chick inner ear development: specification of prosensory patches and lateral inhibition of hair-cell differentiation. Development 132: 541–551.
- 90 Ohtsuka T, Imayoshi I, Shimojo H, Nishi E, Kageyama R, McConnell SK. 2006. Visualization of embryonic neural stem cells using Hes promoters in transgenic mice. Mol Cell Neurosci 31: 109–122.
- 91 Zine A, Aubert A, Qiu J, Therianos S, Guillemot F et al. 2001. Hes1 and Hes5 activities are required for the normal development of the hair cells in the mammalian inner ear. J Neurosci 21: 4712–4720.
- 92 Lanford PJ, Shailam R, Norton CR, Gridley T, Kelley MW. 2000. Expression of Math1 and HES5 in the cochleae of wildtype and Jag2 mutant mice. J Assoc Res Otolaryngol 1: 161–171.
- 93 Ledent V, Vervoort M. 2001. The basic helix-loop-helix protein family: comparative genomics and phylogenetic analysis. Genome Res 11: 754–770.
- 94 Westendorf JJ. 2006. Transcriptional co-repressors of Runx2. J Cell Biochem 98: 54–64.
- 95 Aronson BD, Fisher AL, Blechman K, Caudy M, Gergen JP. 1997. Groucho-dependent and -independent repression activities of Runt domain proteins. Mol Cell Biol 17: 5581–5587.
- 96 Marcal N, Patel H, Dong Z, Belanger-Jasmin S, Hoffman B et al. 2005. Antagonistic effects of Grg6 and Groucho/TLE on the transcription repression activity of brain factor 1/FoxG1 and cortical neuron differentiation. Mol Cell Biol 25: 10916–10929.
- 97 Mitsui K, Shirakata M, Paterson BM. 1993. Phosphorylation inhibits the DNA-binding activity of MyoD homodimers but not MyoD-E12 heterodimers. J Biol Chem 268: 24415–24420.
- 98 Ninkovic J, Tallafuss A, Leucht C, Topczewski J, Tannhauser B et al. 2005. Inhibition of neurogenesis at the zebrafish midbrain-hindbrain boundary by the combined and dose-dependent activity of a new hairy/E(spl) gene pair. Development 132: 75–88.
- 99 Amoutzias GD, Weiner J, Bornberg-Bauer E. 2005. Phylogenetic profiling of protein interaction networks in eukaryotic transcription factors reveals focal proteins being ancestral to hubs. Gene 347: 247–253.
- 100 Amoutzias GD, Robertson DL, Oliver SG, Bornberg-Bauer E. 2004. Convergent evolution of gene networks by single-gene duplications in higher eukaryotes. EMBO Rep 5: 274–279.
- 101 Qian D, Radde-Gallwitz K, Kelly M, Tyrberg B, Kim J et al. 2006. Basic helix-loop-helix gene Hes6 delineates the sensory hair cell lineage in the inner ear. Dev Dyn 235: 1689–1700.
- 102 Koyano-Nakagawa N, Kim J, Anderson D, Kintner C. 2000. Hes6 acts in a positive feedback loop with the neurogenins to promote neuronal differentiation. Development 127: 4203–4216.
- 103 Kang SA, Seol JH, Kim J. 2005. The conserved WRPW motif of Hes6 mediates proteasomal degradation. Biochem Biophys Res Commun 332: –36.
- 104 Louvi A, Artavanis-Tsakonas S. 2006. Notch signalling in vertebrate neural development. Nat Rev Neurosci 7: 93–102.
- 105 Moloney DJ, Panin VM, Johnston SH, Chen J, Shao L et al. 2000. Fringe is a glycosyltransferase that modifies Notch. Nature 406: 369–375.
- 106 Chen P, Segil N. 1999. p27(Kip1) links cell proliferation to morphogenesis in the developing organ of Corti. Development 126: 1581–1590.
- 107 Zhang N, Martin GV, Kelley MW, Gridley T. 2000. A mutation in the Lunatic fringe gene suppresses the effects of a Jagged2 mutation on inner hair cell development in the cochlea. Curr Biol 10: 659–662.
- 108 Yagi M, Kanzaki S, Kawamoto K, Shin B, Shah PP et al. 2000. Spiral ganglion neurons are protected from degeneration by GDNF gene therapy. J Assoc Res Otolaryngol 1: 315–325.
- 109 Matter-Sadzinski L, Puzianowska-Kuznicka M, Hernandez J, Ballivet M, Matter JM. 2005. A bHLH transcriptional network regulating the specification of retinal ganglion cells. Development 132: 3907–3921.
- 110 Szeder V, Grim M, Halata Z, Sieber-Blum M. 2003. Neural crest origin of mammalian Merkel cells. Dev Biol 253: 258–263.
- 111 Hertzano R, Montcouquiol M, Rashi-Elkeles S, Elkon R, Yucel R et al. 2004. Transcription profiling of inner ears from Pou4f3(ddl/ddl) identifies Gfi1 as a target of the Pou4f3 deafness gene. Hum Mol Genet 13: 2143–2153.
- 112 Xiang M, Maklad A, Pirvola U, Fritzsch B. 2003. Brn3c null mutant mice show long-term, incomplete retention of some afferent inner ear innervation. BMC Neurosci 4: 2.
- 113 Haeberle H, Fujiwara M, Chuang J, Medina MM, Panditrao MV et al. 2004. Molecular profiling reveals synaptic release machinery in Merkel cells. Proc Natl Acad Sci USA 101: 14503–14508.
- 114 Leonard JH, Cook AL, Van Gele M, Boyle GM, Inglis KJ et al. 2002. Proneural and proneuroendocrine transcription factor expression in cutaneous mechanoreceptor (Merkel) cells and Merkel cell carcinoma. Int J Cancer 101: 103–110.
- 115 Ben-Arie N, Hassan BA, Bermingham NA, Malicki DM, Armstrong D et al. 2000. Functional conservation of atonal and Math1 in the CNS and PNS. Development 127: 1039–1048.
- 116 Cau E, Casarosa S, Guillemot F. 2002. Mash1 and Ngn1 control distinct steps of determination and differentiation in the olfactory sensory neuron lineage. Development 129: 1871–1880.
- 117 Conrad R, Barrier M, Ford LP. 2006. Role of miRNA and miRNA processing factors in development and disease. Birth Defects Res C Embryo Today 78: 107–117.
- 118 Weston MD, Pierce ML, Rocha-Sanchez S, Beisel KW, Soukup GA. 2006. MicroRNA gene expression in the mouse inner ear. Brain Res 1111: 95–104.
- 119 Andl T, Murchison EP, Liu F, Zhang Y, Yunta-Gonzalez M et al. 2006. The miRNA-processing enzyme dicer is essential for the morphogenesis and maintenance of hair follicles. Curr Biol 16: 1041–1049.
- 120 Fekete DM, Wu DK. 2002. Revisiting cell fate specification in the inner ear. Curr Opin Neurobiol 12: 35–42.
