Skip to main content

Advertisement

SpringerLink
Log in

Spatial and Age-Dependent Hair Cell Generation in the Postnatal Mammalian Utricle

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Loss of vestibular hair cells is a common cause of balance disorders. Current treatment options for bilateral vestibular dysfunction are limited. During development, atonal homolog 1 (Atoh1) is sufficient and necessary for the formation of hair cells and provides a promising gene target to induce hair cell generation in the mammals. In this study, we used a transgenic mouse line to test the age and cell type specificity of hair cell induction in the postnatal utricle in mice. We found that forced Atoh1 expression in vivo can induce hair cell formation in the utricle from postnatal days 1 to 21, while the efficacy of hair cell induction is progressively reduced as the animals become older. In the utricle, the induction of hair cells occurs both within the sensory region and in cells in the transitional epithelium next to the sensory region. Within the sensory epithelium, the central region, known as the striola, is most subjective to the induction of hair cell formation. Furthermore, forced Atoh1 expression can promote proliferation in an age-dependent manner that mirrors the progressively reduced efficacy of hair cell induction in the postnatal utricle. These results suggest that targeting both cell proliferation and Atoh1 in the utricle striolar region may be explored to induce hair cell regeneration in mammals. The study also demonstrates the usefulness of the animal model that provides an in vivo Atoh1 induction model for vestibular regeneration studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Baker K, Brough DE, Staecker H (2009) Repair of the vestibular system via adenovector delivery of Atoh1: a potential treatment for balance disorders. Adv Otorhinolaryngol 66:52–63. doi:10.1159/000218207

    CAS  PubMed  Google Scholar 

  2. Proctor L, Perlman H, Lindsay J, Matz G (1979) Acute vestibular paralysis in herpes zoster oticus. Ann Otol Rhinol Laryngol 88(3 Pt 1):303–310

    Article  CAS  PubMed  Google Scholar 

  3. Tsuji K, Velazquez-Villasenor L, Rauch SD, Glynn RJ, Wall C 3rd, Merchant SN (2000) Temporal bone studies of the human peripheral vestibular system. Aminoglycoside ototoxicity. Ann Otol Rhinol Laryngol Suppl 181:20–25

    Article  CAS  PubMed  Google Scholar 

  4. Tsuji K, Velazquez-Villasenor L, Rauch SD, Glynn RJ, Wall C 3rd, Merchant SN (2000) Temporal bone studies of the human peripheral vestibular system. Meniere's disease. Ann Otol Rhinol Laryngol Suppl 181:26–31

    Article  CAS  PubMed  Google Scholar 

  5. Barin K, Dodson EE (2011) Dizziness in the elderly. Otolaryngol Clin North Am 44(2):437–454. doi:10.1016/j.otc.2011.01.013, x

    Article  PubMed  Google Scholar 

  6. Vidal PP, de Waele C, Vibert N, Muhlethaler M (1998) Vestibular compensation revisited. Otolaryngol Head Neck Surg 119(1):34–42

    Article  CAS  PubMed  Google Scholar 

  7. Gillespie MB, Minor LB (1999) Prognosis in bilateral vestibular hypofunction. Laryngoscope 109(1):35–41

    Article  CAS  PubMed  Google Scholar 

  8. Albu S, Muresanu DF (2012) Vestibular regeneration–experimental models and clinical implications. J Cell Mol Med 16(9):1970–1977. doi:10.1111/j.1582-4934.2012.01540.x

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kawamoto K, Izumikawa M, Beyer LA, Atkin GM, Raphael Y (2009) Spontaneous hair cell regeneration in the mouse utricle following gentamicin ototoxicity. Hear Res 247(1):17–26. doi:10.1016/j.heares.2008.08.010

    Article  CAS  PubMed  Google Scholar 

  10. Forge A, Li L, Corwin JT, Nevill G (1993) Ultrastructural evidence for hair cell regeneration in the mammalian inner ear. Science 259(5101):1616–1619

    Article  CAS  PubMed  Google Scholar 

  11. Tanyeri H, Lopez I, Honrubia V (1995) Histological evidence for hair cell regeneration after ototoxic cell destruction with local application of gentamicin in the chinchilla crista ampullaris. Hear Res 89(1–2):194–202

    Article  CAS  PubMed  Google Scholar 

  12. Berggren D, Liu W, Frenz D, Van De Water T (2003) Spontaneous hair-cell renewal following gentamicin exposure in postnatal rat utricular explants. Hear Res 180(1-2):114–125

    Article  CAS  PubMed  Google Scholar 

  13. Bermingham NA, Hassan BA, Price SD, Vollrath MA, Ben-Arie N, Eatock RA, Bellen HJ, Lysakowski A, Zoghbi HY (1999) Math1: an essential gene for the generation of inner ear hair cells. Science 284(5421):1837–1841

    Article  CAS  PubMed  Google Scholar 

  14. Chen P, Johnson JE, Zoghbi HY, Segil N (2002) The role of Math1 in inner ear development: Uncoupling the establishment of the sensory primordium from hair cell fate determination. Development (Cambridge, England) 129(10):2495–2505

    CAS  Google Scholar 

  15. Gubbels SP, Woessner DW, Mitchell JC, Ricci AJ, Brigande JV (2008) Functional auditory hair cells produced in the mammalian cochlea by in utero gene transfer. Nature 455(7212):537–541. doi:10.1038/nature07265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Woods C, Montcouquiol M, Kelley MW (2004) Math1 regulates development of the sensory epithelium in the mammalian cochlea. Nat Neurosci 7(12):1310–1318. doi:10.1038/nn1349

    Article  CAS  PubMed  Google Scholar 

  17. Zheng JL, Gao WQ (2000) Overexpression of Math1 induces robust production of extra hair cells in postnatal rat inner ears. Nat Neurosci 3(6):580–586. doi:10.1038/75753

    Article  CAS  PubMed  Google Scholar 

  18. Izumikawa M, Minoda R, Kawamoto K, Abrashkin KA, Swiderski DL, Dolan DF, Brough DE, Raphael Y (2005) Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nat Med 11(3):271–276. doi:10.1038/nm1193

    Article  CAS  PubMed  Google Scholar 

  19. Kawamoto K, Ishimoto S, Minoda R, Brough DE, Raphael Y (2003) Math1 gene transfer generates new cochlear hair cells in mature guinea pigs in vivo. J Neurosci 23(11):4395–4400

    CAS  PubMed  Google Scholar 

  20. Schlecker C, Praetorius M, Brough DE, Presler RG Jr, Hsu C, Plinkert PK, Staecker H (2011) Selective atonal gene delivery improves balance function in a mouse model of vestibular disease. Gene Ther 18(9):884–890. doi:10.1038/gt.2011.33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shou J, Zheng JL, Gao WQ (2003) Robust generation of new hair cells in the mature mammalian inner ear by adenoviral expression of Hath1. Mol Cell Neurosci 23(2):169–179

    Article  CAS  PubMed  Google Scholar 

  22. Staecker H, Praetorius M, Baker K, Brough DE (2007) Vestibular hair cell regeneration and restoration of balance function induced by math1 gene transfer. Otol Neurotol 28(2):223–231. doi:10.1097/MAO.0b013e31802b3225

    Article  PubMed  Google Scholar 

  23. Kelly MC, Chang Q, Pan A, Lin X, Chen P (2012) Atoh1 directs the formation of sensory mosaics and induces cell proliferation in the postnatal mammalian cochlea in vivo. J Neurosci 32(19):6699–6710. doi:10.1523/jneurosci. 5420-11.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Belteki G, Haigh J, Kabacs N, Haigh K, Sison K, Costantini F, Whitsett J, Quaggin SE, Nagy A (2005) Conditional and inducible transgene expression in mice through the combinatorial use of Cre-mediated recombination and tetracycline induction. Nucleic Acids Res 33(5):e51. doi:10.1093/nar/gni051

    Article  PubMed  PubMed Central  Google Scholar 

  25. Hebert JM, McConnell SK (2000) Targeting of cre to the Foxg1 (BF-1) locus mediates loxP recombination in the telencephalon and other developing head structures. Dev Biol 222(2):296–306. doi:10.1006/dbio.2000.9732

    Article  CAS  PubMed  Google Scholar 

  26. Lumpkin EA, Collisson T, Parab P, Omer-Abdalla A, Haeberle H, Chen P, Doetzlhofer A, White P, Groves A, Segil N, Johnson JE (2003) Math1-driven GFP expression in the developing nervous system of transgenic mice. Gene Expr Patterns 3(4):389–395

    Article  CAS  PubMed  Google Scholar 

  27. Chen P, Segil N (1999) p27(Kip1) links cell proliferation to morphogenesis in the developing organ of Corti. Development (Cambridge, England) 126(8):1581–1590

    CAS  Google Scholar 

  28. Li S, Mark S, Radde-Gallwitz K, Schlisner R, Chin MT, Chen P (2008) Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development. BMC Dev Biol 8:20. doi:10.1186/1471-213x-8-20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tang X, Falls DL, Li X, Lane T, Luskin MB (2007) Antigen-retrieval procedure for bromodeoxyuridine immunolabeling with concurrent labeling of nuclear DNA and antigens damaged by HCl pretreatment. J Neurosci 27(22):5837–5844. doi:10.1523/jneurosci. 5048-06.2007

    Article  CAS  PubMed  Google Scholar 

  30. Huang Y, Chi F, Han Z, Yang J, Gao W, Li Y (2009) New ectopic vestibular hair cell-like cells induced by Math1 gene transfer in postnatal rats. Brain Res 1276:31–38. doi:10.1016/j.brainres.2009.04.036

    Article  CAS  PubMed  Google Scholar 

  31. Lin V, Golub JS, Nguyen TB, Hume CR, Oesterle EC, Stone JS (2011) Inhibition of Notch activity promotes nonmitotic regeneration of hair cells in the adult mouse utricles. J Neurosci 31(43):15329–15339. doi:10.1523/jneurosci. 2057-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Staecker H, Schlecker C, Kraft S, Praetorius M, Hsu C, Brough DE (2014) Optimizing atoh1-induced vestibular hair cell regeneration. Laryngoscope 124(Suppl 5):S1–S12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Collado MS, Thiede BR, Baker W, Askew C, Igbani LM, Corwin JT (2011) The postnatal accumulation of junctional E-cadherin is inversely correlated with the capacity for supporting cells to convert directly into sensory hair cells in mammalian balance organs. J Neurosci 31(33):11855–11866. doi:10.1523/jneurosci. 2525-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Warchol ME, Lambert PR, Goldstein BJ, Forge A, Corwin JT (1993) Regenerative proliferation in inner ear sensory epithelia from adult guinea pigs and humans. Science 259(5101):1619–1622

    Article  CAS  PubMed  Google Scholar 

  35. Forge A, Li L, Nevill G (1998) Hair cell recovery in the vestibular sensory epithelia of mature guinea pigs. J Comp Neurol 397(1):69–88

    Article  CAS  PubMed  Google Scholar 

  36. Li L, Forge A (1997) Morphological evidence for supporting cell to hair cell conversion in the mammalian utricular macula. Int J Dev Neurosci 15(4–5):433–446

    Article  CAS  PubMed  Google Scholar 

  37. Li L, Nevill G, Forge A (1995) Two modes of hair cell loss from the vestibular sensory epithelia of the guinea pig inner ear. J Comp Neurol 355(3):405–417. doi:10.1002/cne.903550307

    Article  CAS  PubMed  Google Scholar 

  38. Werner M, Van De Water TR, Andersson T, Arnoldsson G, Berggren D (2012) Morphological and morphometric characteristics of vestibular hair cells and support cells in long term cultures of rat utricle explants. Hear Res 283(1-2):107–116. doi:10.1016/j.heares.2011.11.003

    Article  PubMed  Google Scholar 

  39. Zheng JL, Keller G, Gao WQ (1999) Immunocytochemical and morphological evidence for intracellular self-repair as an important contributor to mammalian hair cell recovery. J Neurosci 19(6):2161–2170

    CAS  PubMed  Google Scholar 

  40. Ruben RJ (1967) Development of the inner ear of the mouse: a radioautographic study of terminal mitoses. Acta oto-laryngologica:Suppl 220:221–244

    Google Scholar 

  41. Wang J, Mark S, Zhang X, Qian D, Yoo SJ, Radde-Gallwitz K, Zhang Y, Lin X, Collazo A, Wynshaw-Boris A, Chen P (2005) Regulation of polarized extension and planar cell polarity in the cochlea by the vertebrate PCP pathway. Nat Genet 37(9):980–985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Suzuki M, Yamasoba T, Kaga K (1998) Development of the blood-labyrinth barrier in the rat. Hear Res 116(1–2):107–112

    Article  CAS  PubMed  Google Scholar 

  43. Cox BC, Dearman JA, Brancheck J, Zindy F, Roussel MF, Zuo J (2014) Generation of Atoh1-rtTA transgenic mice: a tool for inducible gene expression in hair cells of the inner ear. Scientific Reports 4:6885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kopke RD, Jackson RL, Li G, Rasmussen MD, Hoffer ME, Frenz DA, Costello M, Schultheiss P, Van De Water TR (2001) Growth factor treatment enhances vestibular hair cell renewal and results in improved vestibular function. Proc Natl Acad Sci U S A 98(10):5886–5891. doi:10.1073/pnas.101120898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank laboratory members for helpful discussions. This work was supported by National Institutes of Health (NIH)–National Institute on Deafness and Other Communication Disorders Grant R01 DC05213 and in part by National Natural Science Foundation of China Grant 81271084, Natural Science Foundation of China Grant 81420108010 and Natural Science Foundation of China Grant 81400460.

Author information

Authors and Affiliations

  1. Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia, 30322, USA

    Zhen Gao, Michael C. Kelly, Xi Lin & Ping Chen

  2. Department of Otology and Skull Base Surgery, Eye and ENT Hospital, Fudan University, Shanghai, 200031, China

    Zhen Gao & Fang-lu Chi

  3. Department of Otolaryngology-Head and Neck Surgery, Xinhua Hospital and Ear Institute, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Dehong Yu & Hao Wu

  4. Department of Otolaryngology, Emory University School of Medicine, Atlanta, Georgia, 30322, USA

    Xi Lin

Authors
  1. Zhen Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael C. Kelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dehong Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xi Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fang-lu Chi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ping Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Fang-lu Chi or Ping Chen.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Fig. S1

Atoh1 induction is permanently poised in Foxg1-expressing cells. (A-B) GFP expression (A) under the expression cassette of rtTA-IRES-GFP is permanently activated in cells of the Foxg1-Cre lineage as diagramed in figure 1. At P21, Atoh1 expression reporter, Atoh1-nGFP, is expressed throughout the utricle epithelium including the sensory and transitional epithelia upon induction condition (Dox feeding) (B). Tri-allelic label indicates that the animals carry rtTA, Foxg1-Cre and TgAtoh1 alleles. Scale: 100 μm (A); 25 μm (B). (JPEG 3737 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gao, Z., Kelly, M.C., Yu, D. et al. Spatial and Age-Dependent Hair Cell Generation in the Postnatal Mammalian Utricle. Mol Neurobiol 53, 1601–1612 (2016). https://doi.org/10.1007/s12035-015-9119-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-015-9119-0

Keywords

Search

Navigation