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Research Overview

We have an active research group focused on the function and dysfunction of the inner ear.  Our goal is to understand how stimuli from the external world, such as sound, gravity and head movements are converted into electrical signals, how the information is encoded and how it is transmitted to the brain. Furthermore, we want to understand why genetic mutations cause hearing and balance dysfunction.  We plan to use this information to design novel therapeutic innervations for deafness and balance disorders.

Sensory transduction in the ear beings with deflection of mechanosensitive organelles that project from the apical surface of inner ear hair cells.  The exquisite sensitivity of the auditory system can initiate signals that encode the faint pizzicato of a classical violin.  Remarkably, auditory hair cells can also detect stimuli with amplitudes over a million times greater, and thus can signal the booming cannons of Tchaikovsky's 1812 Overture as well. This extraordinary dynamic range is the result of a sensory transduction process that utilizes several feedback mechanisms to precisely reposition and tune the mechanosensitive apparatus within the optimal range allowing detection of auditory stimuli that span the breadth of amplitudes and frequencies humans encounter daily.

Ongoing projects in the lab include the study of:
  • Mechanotransduction and adaptation in sensory hair cells
  • Firing properties of afferent neurons that relay information to the brain
  • Development of inner ear function
  • Novel gene therapy strategies to treat inner ear dysfunction

About Jeffrey Holt

Jeffrey Holt received a PhD from the University of Rochester in 1995.  He completed a postdoctoral fellowship with the Howard Hughes Medical Institute at Harvard Medical School in the laboratory of David Corey.  In 2001 Dr. Holt accepted a faculty position in the Department of Neuroscience at the University of Virginia.  In 2011 he returned to Harvard to join the Department of Otolaryngology, the F.M. Kirby Neurobiology Center and the Neurobiology Program at Boston Children’s Hospital. Dr. Holt was promoted to Professor of Otolaryngology at Harvard Medical School in 2016.

Key Publications

  • Gao X, Tao Y, Lamas V, Huang M, Yeh WH, Pan B, Hu YJ, Hu JH, Thompson DB, Shu Y, Li Y, Wang H, Yang S, Xu Q, Polley DB, Liberman MC, Kong WJ, Holt JR, Chen ZY, Liu DR. Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents. Nature. 2018
  • Koehler KR, Nie J, Longworth-Mills E, Liu XP, Lee J, Holt JR, Hashino E. Generation of inner ear organoids containing functional hair cells from human pluripotent stem cells. Nat Biotechnol. 2017 Jun; 35(6):583-589.
  • Pan B, Askew C, Galvin A, Heman-Ackah S, Asai Y, Indzhykulian AA, Jodelka FM, Hastings ML, Lentz JJ, Vandenberghe LH, Holt JR, Géléoc GS. Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c. Nat Biotechnol. 2017 Mar; 35(3):264-272.
  • Corey DP, Holt JR. Are TMCs the Mechanotransduction Channels of Vertebrate Hair Cells? J Neurosci. 2016 Oct 26; 36(43):10921-10926.
  • Liu XP, Koehler KR, Mikosz AM, Hashino E, Holt JR. Functional development of mechanosensitive hair cells in stem cell-derived organoids parallels native vestibular hair cells. Nature Com.. 7:11508, 2016
  • Akyuz N, Holt JR. Plug-N-Play: Mechanotransduction Goes Modular. Neuron. 89(6):1128-30, 2016.
  • Askew C, Rochat C, Pan B, Asai Y, Ahmed H, Child E, Schneider BL, Aebischer P, Holt JR. Tmc gene therapy restores auditory function in deaf mice. Science Translational Medicine. 7(295):295ra108, 2015.
  • Géléoc GS, Holt JR. Sound strategies for hearing restoration. Science. 344(6184):1241062. 2014
  • Pan B, Géléoc GS, Asai Y, Horwitz GC, Kurima K, Ishikawa K, Kawashima Y, Griffith AJ, Holt JR. TMC1 and TMC2 are components of the mechanotransduction channel in hair cells of the mammalian inner ear. Neuron. 79(3):504-15, 2013.
  • Kawashima Y, Géléoc GS, Kurima K, Labay V, Lelli A, Asai Y, Makishima T, Wu DK, Della Santina CC, Holt JR, Griffith AJ. Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes. J Clinical Investigation. 121(12):4796-809, 2011.

Researcher Services

Researcher Areas

  • Molecular Basis of Sensory Signals in Hearing and Deafness

Research Departments

Researcher Programs

Researcher Centers

Researcher Labs

PUBLICATIONS

Publications powered by Harvard Catalyst Profiles

  1. Gao X, Tao Y, Lamas V, Huang M, Yeh WH, Pan B, Hu YJ, Hu JH, Thompson DB, Shu Y, Li Y, Wang H, Yang S, Xu Q, Polley DB, Liberman MC, Kong WJ, Holt JR, Chen ZY, Liu DR. Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents. Nature. 2018 Jan 11; 553(7687):217-221. View abstract
  2. Ahmed H, Shubina-Oleinik O, Holt JR. Emerging Gene Therapies for Genetic Hearing Loss. J Assoc Res Otolaryngol. 2017 Oct; 18(5):649-670. View abstract
  3. Koehler KR, Nie J, Longworth-Mills E, Liu XP, Lee J, Holt JR, Hashino E. Generation of inner ear organoids containing functional hair cells from human pluripotent stem cells. Nat Biotechnol. 2017 06; 35(6):583-589. View abstract
  4. Landegger LD, Pan B, Askew C, Wassmer SJ, Gluck SD, Galvin A, Taylor R, Forge A, Stankovic KM, Holt JR, Vandenberghe LH. A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear. Nat Biotechnol. 2017 03; 35(3):280-284. View abstract
  5. Pan B, Askew C, Galvin A, Heman-Ackah S, Asai Y, Indzhykulian AA, Jodelka FM, Hastings ML, Lentz JJ, Vandenberghe LH, Holt JR, Géléoc GS. Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c. Nat Biotechnol. 2017 03; 35(3):264-272. View abstract
  6. Corey DP, Holt JR. Are TMCs the Mechanotransduction Channels of Vertebrate Hair Cells? J Neurosci. 2016 Oct 26; 36(43):10921-10926. View abstract
  7. Shibata SB, Ranum PT, Moteki H, Pan B, Goodwin AT, Goodman SS, Abbas PJ, Holt JR, Smith RJH. RNA Interference Prevents Autosomal-Dominant Hearing Loss. Am J Hum Genet. 2016 06 02; 98(6):1101-1113. View abstract
  8. Liu XP, Koehler KR, Mikosz AM, Hashino E, Holt JR. Functional development of mechanosensitive hair cells in stem cell-derived organoids parallels native vestibular hair cells. Nat Commun. 2016 May 24; 7:11508. View abstract
  9. Akyuz N, Holt JR. Plug-N-Play: Mechanotransduction Goes Modular. Neuron. 2016 Mar 16; 89(6):1128-1130. View abstract
  10. Imtiaz A, Maqsood A, Rehman AU, Morell RJ, Holt JR, Friedman TB, Naz S. Recessive mutations of TMC1 associated with moderate to severe hearing loss. Neurogenetics. 2016 Apr; 17(2):115-123. View abstract
  11. Kurima K, Ebrahim S, Pan B, Sedlacek M, Sengupta P, Millis BA, Cui R, Nakanishi H, Fujikawa T, Kawashima Y, Choi BY, Monahan K, Holt JR, Griffith AJ, Kachar B. TMC1 and TMC2 Localize at the Site of Mechanotransduction in Mammalian Inner Ear Hair Cell Stereocilia. Cell Rep. 2015 Sep 08; 12(10):1606-17. View abstract
  12. Pan B, Holt JR. The molecules that mediate sensory transduction in the mammalian inner ear. Curr Opin Neurobiol. 2015 Oct; 34:165-71. View abstract
  13. Askew C, Rochat C, Pan B, Asai Y, Ahmed H, Child E, Schneider BL, Aebischer P, Holt JR. Tmc gene therapy restores auditory function in deaf mice. Sci Transl Med. 2015 Jul 08; 7(295):295ra108. View abstract
  14. Kawashima Y, Kurima K, Pan B, Griffith AJ, Holt JR. Transmembrane channel-like (TMC) genes are required for auditory and vestibular mechanosensation. Pflugers Arch. 2015 Jan; 467(1):85-94. View abstract
  15. Géléoc GS, Holt JR. Sound strategies for hearing restoration. Science. 2014 May 09; 344(6184):1241062. View abstract
  16. Horwitz GC, Risner-Janiczek JR, Holt JR. Mechanotransduction and hyperpolarization-activated currents contribute to spontaneous activity in mouse vestibular ganglion neurons. J Gen Physiol. 2014 Apr; 143(4):481-97. View abstract
  17. Holt JR, Pan B, Koussa MA, Asai Y. TMC function in hair cell transduction. Hear Res. 2014 May; 311:17-24. View abstract
  18. Zou J, Zheng T, Ren C, Askew C, Liu XP, Pan B, Holt JR, Wang Y, Yang J. Deletion of PDZD7 disrupts the Usher syndrome type 2 protein complex in cochlear hair cells and causes hearing loss in mice. Hum Mol Genet. 2014 May 01; 23(9):2374-90. View abstract
  19. Yu WM, Appler JM, Kim YH, Nishitani AM, Holt JR, Goodrich LV. A Gata3-Mafb transcriptional network directs post-synaptic differentiation in synapses specialized for hearing. Elife. 2013 Dec 10; 2:e01341. View abstract
  20. Kim YH, Holt JR. Functional contributions of HCN channels in the primary auditory neurons of the mouse inner ear. J Gen Physiol. 2013 Sep; 142(3):207-23. View abstract
  21. Pan B, Géléoc GS, Asai Y, Horwitz GC, Kurima K, Ishikawa K, Kawashima Y, Griffith AJ, Holt JR. TMC1 and TMC2 are components of the mechanotransduction channel in hair cells of the mammalian inner ear. Neuron. 2013 Aug 07; 79(3):504-15. View abstract
  22. Holt JR, Vandenberghe LH. Gene therapy for deaf mice goes viral. Mol Ther. 2012 Oct; 20(10):1836-7. View abstract
  23. Geng R, Melki S, Chen DH, Tian G, Furness DN, Oshima-Takago T, Neef J, Moser T, Askew C, Horwitz G, Holt JR, Imanishi Y, Alagramam KN. The mechanosensory structure of the hair cell requires clarin-1, a protein encoded by Usher syndrome III causative gene. J Neurosci. 2012 Jul 11; 32(28):9485-98. View abstract
  24. Levin ME, Holt JR. The function and molecular identity of inward rectifier channels in vestibular hair cells of the mouse inner ear. J Neurophysiol. 2012 Jul; 108(1):175-86. View abstract
  25. Kawashima Y, Géléoc GS, Kurima K, Labay V, Lelli A, Asai Y, Makishima T, Wu DK, Della Santina CC, Holt JR, Griffith AJ. Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes. J Clin Invest. 2011 Dec; 121(12):4796-809. View abstract
  26. Horwitz GC, Risner-Janiczek JR, Jones SM, Holt JR. HCN channels expressed in the inner ear are necessary for normal balance function. J Neurosci. 2011 Nov 16; 31(46):16814-25. View abstract
  27. Steigelman KA, Lelli A, Wu X, Gao J, Lin S, Piontek K, Wodarczyk C, Boletta A, Kim H, Qian F, Germino G, Géléoc GS, Holt JR, Zuo J. Polycystin-1 is required for stereocilia structure but not for mechanotransduction in inner ear hair cells. J Neurosci. 2011 Aug 24; 31(34):12241-50. View abstract
  28. Charizopoulou N, Lelli A, Schraders M, Ray K, Hildebrand MS, Ramesh A, Srisailapathy CR, Oostrik J, Admiraal RJ, Neely HR, Latoche JR, Smith RJ, Northup JK, Kremer H, Holt JR, Noben-Trauth K. Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human. Nat Commun. 2011 Feb 15; 2:201. View abstract
  29. Lelli A, Kazmierczak P, Kawashima Y, Müller U, Holt JR. Development and regeneration of sensory transduction in auditory hair cells requires functional interaction between cadherin-23 and protocadherin-15. J Neurosci. 2010 Aug 25; 30(34):11259-69. View abstract
  30. Horwitz GC, Lelli A, Géléoc GS, Holt JR. HCN channels are not required for mechanotransduction in sensory hair cells of the mouse inner ear. PLoS One. 2010 Jan 07; 5(1):e8627. View abstract
  31. Asai Y, Holt JR, Géléoc GS. A quantitative analysis of the spatiotemporal pattern of transient receptor potential gene expression in the developing mouse cochlea. J Assoc Res Otolaryngol. 2010 Mar; 11(1):27-37. View abstract
  32. Li H, Liu H, Corrales CE, Risner JR, Forrester J, Holt JR, Heller S, Edge AS. Differentiation of neurons from neural precursors generated in floating spheres from embryonic stem cells. BMC Neurosci. 2009 Sep 24; 10:122. View abstract
  33. Lelli A, Asai Y, Forge A, Holt JR, Géléoc GS. Tonotopic gradient in the developmental acquisition of sensory transduction in outer hair cells of the mouse cochlea. J Neurophysiol. 2009 Jun; 101(6):2961-73. View abstract
  34. Schwander M, Xiong W, Tokita J, Lelli A, Elledge HM, Kazmierczak P, Sczaniecka A, Kolatkar A, Wiltshire T, Kuhn P, Holt JR, Kachar B, Tarantino L, Müller U. A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells. Proc Natl Acad Sci U S A. 2009 Mar 31; 106(13):5252-7. View abstract
  35. Collado MS, Holt JR. Can neurosphere production help restore inner ear transduction? Proc Natl Acad Sci U S A. 2009 Jan 06; 106(1):8-9. View abstract
  36. Kesser BW, Hashisaki GT, Holt JR. Gene transfer in human vestibular epithelia and the prospects for inner ear gene therapy. Laryngoscope. 2008 May; 118(5):821-31. View abstract
  37. Stauffer EA, Holt JR. Sensory transduction and adaptation in inner and outer hair cells of the mouse auditory system. J Neurophysiol. 2007 Dec; 98(6):3360-9. View abstract
  38. Holt JR, Stauffer EA, Abraham D, Géléoc GS. Dominant-negative inhibition of M-like potassium conductances in hair cells of the mouse inner ear. J Neurosci. 2007 Aug 15; 27(33):8940-51. View abstract
  39. Oshima K, Grimm CM, Corrales CE, Senn P, Martinez Monedero R, Géléoc GS, Edge A, Holt JR, Heller S. Differential distribution of stem cells in the auditory and vestibular organs of the inner ear. J Assoc Res Otolaryngol. 2007 Mar; 8(1):18-31. View abstract
  40. Risner JR, Holt JR. Heterogeneous potassium conductances contribute to the diverse firing properties of postnatal mouse vestibular ganglion neurons. J Neurophysiol. 2006 Nov; 96(5):2364-76. View abstract
  41. McGee J, Goodyear RJ, McMillan DR, Stauffer EA, Holt JR, Locke KG, Birch DG, Legan PK, White PC, Walsh EJ, Richardson GP. The very large G-protein-coupled receptor VLGR1: a component of the ankle link complex required for the normal development of auditory hair bundles. J Neurosci. 2006 Jun 14; 26(24):6543-53. View abstract
  42. Senften M, Schwander M, Kazmierczak P, Lillo C, Shin JB, Hasson T, Géléoc GS, Gillespie PG, Williams D, Holt JR, Müller U. Physical and functional interaction between protocadherin 15 and myosin VIIa in mechanosensory hair cells. J Neurosci. 2006 Feb 15; 26(7):2060-71. View abstract
  43. Stauffer EA, Scarborough JD, Hirono M, Miller ED, Shah K, Mercer JA, Holt JR, Gillespie PG. Fast adaptation in vestibular hair cells requires myosin-1c activity. Neuron. 2005 Aug 18; 47(4):541-53. View abstract
  44. Géléoc GS, Risner JR, Holt JR. Developmental acquisition of voltage-dependent conductances and sensory signaling in hair cells of the embryonic mouse inner ear. J Neurosci. 2004 Dec 08; 24(49):11148-59. View abstract
  45. Corey DP, García-Añoveros J, Holt JR, Kwan KY, Lin SY, Vollrath MA, Amalfitano A, Cheung EL, Derfler BH, Duggan A, Géléoc GS, Gray PA, Hoffman MP, Rehm HL, Tamasauskas D, Zhang DS. TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells. Nature. 2004 Dec 09; 432(7018):723-30. View abstract
  46. Géléoc GS, Holt JR. Developmental acquisition of sensory transduction in hair cells of the mouse inner ear. Nat Neurosci. 2003 Oct; 6(10):1019-20. View abstract
  47. Colclasure JC, Holt JR. Transduction and adaptation in sensory hair cells of the mammalian vestibular system. Gravit Space Biol Bull. 2003 Jun; 16(2):61-70. View abstract
  48. Géléoc GS, Holt JR. Auditory amplification: outer hair cells pres the issue. Trends Neurosci. 2003 Mar; 26(3):115-7. View abstract
  49. Holt JR. Viral-mediated gene transfer to study the molecular physiology of the Mammalian inner ear. Audiol Neurootol. 2002 May-Jun; 7(3):157-60. View abstract
  50. Dumont RA, Zhao YD, Holt JR, Bähler M, Gillespie PG. Myosin-I isozymes in neonatal rodent auditory and vestibular epithelia. J Assoc Res Otolaryngol. 2002 Dec; 3(4):375-89. View abstract
  51. Holt JR, Gillespie SK, Provance DW, Shah K, Shokat KM, Corey DP, Mercer JA, Gillespie PG. A chemical-genetic strategy implicates myosin-1c in adaptation by hair cells. Cell. 2002 Feb 08; 108(3):371-81. View abstract
  52. Holt JR, Corey DP. Two mechanisms for transducer adaptation in vertebrate hair cells. Proc Natl Acad Sci U S A. 2000 Oct 24; 97(22):11730-5. View abstract
  53. Holt JR, Vollrath MA, Eatock RA. Stimulus processing by type II hair cells in the mouse utricle. Ann N Y Acad Sci. 1999 May 28; 871:15-26. View abstract
  54. Holt JR. Biology in pictures. A sense of colour. Curr Biol. 1999 May 20; 9(10):R351. View abstract
  55. Holt JR, Johns DC, Wang S, Chen ZY, Dunn RJ, Marban E, Corey DP. Functional expression of exogenous proteins in mammalian sensory hair cells infected with adenoviral vectors. J Neurophysiol. 1999 Apr; 81(4):1881-8. View abstract
  56. Holt JR, Corey DP. Ion channel defects in hereditary hearing loss. Neuron. 1999 Feb; 22(2):217-9. View abstract
  57. Holt JR, Corey DP, Eatock RA. Mechanoelectrical transduction and adaptation in hair cells of the mouse utricle, a low-frequency vestibular organ. J Neurosci. 1997 Nov 15; 17(22):8739-48. View abstract