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Jeffrey  Holt, PhD

Jeffrey Holt
Lab:
Holt/Geleoc Laboratory
Research Center:
F.M. Kirby Neurobiology Center
Program:
Neurobiology Program
Department:
Otolaryngology and Communication Enhancement ResearchNeurology Research
Hospital Title:
Research Associate in Otolaryngology and Neurology
Academic Title:
Professor of Otolaryngology, Harvard Medical School
Research Focus Area:
Molecular basis of sensory signals in hearing and deafness
Contact:
617-919-3574
Contact Via Email
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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

  • 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.
  • Pan B, Holt JR. The molecules that mediate sensory transduction in the mammalian inner ear. Curr Opin Neurobiol. 34:165-71, 2015.
  • Géléoc GS, Holt JR. Sound strategies for hearing restoration. Science. 344(6184):1241062. 2014.
  • Horwitz GC, Risner-Janiczek JR, Holt JR. Mechanotransduction and hyperpolarization-activated currents contribute to spontaneous activity in mouse vestibular ganglion neurons. J Gen Physiol. 143(4):481-97, 2014.
  • Kim YH, Holt JR. Functional contributions of HCN channels in the primary auditory neurons of the mouse inner ear. J Gen Physiol. 142(3):207-23, 2013.
  • 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.
  • Levin ME, Holt JR. The function and molecular identity of inward rectifier channels in vestibular hair cells of the mouse inner ear. J Neurophysiol. 108(1):175-86, 2012.
  • 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.

Publications

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  1. Shibata SB, Ranum PT, Moteki H, Pan B, Goodwin AT, Goodman SS, Abbas PJ, Holt JR, Smith RJ. RNA Interference Prevents Autosomal-Dominant Hearing Loss. Am J Hum Genet. 2016 Jun 2; 98(6):1101-13.
  2. 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.
  3. Akyuz N, Holt JR. Plug-N-Play: Mechanotransduction Goes Modular. Neuron. 2016 Mar 16; 89(6):1128-30.
  4. Pan B, Holt JR. The molecules that mediate sensory transduction in the mammalian inner ear. Curr Opin Neurobiol. 2015 Oct; 34:165-71.
  5. 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 8; 7(295):295ra108.
  6. Géléoc GS, Holt JR. Sound strategies for hearing restoration. Science. 2014 May 9; 344(6184):1241062.
  7. 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.
  8. Holt JR, Pan B, Koussa MA, Asai Y. TMC function in hair cell transduction. Hear Res. 2014 May; 311:17-24.
  9. 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 1; 23(9):2374-90.
  10. 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.
  11. Show all
  12. Holt JR, Vandenberghe LH. Gene therapy for deaf mice goes viral. Mol Ther. 2012 Oct; 20(10):1836-7.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. Collado MS, Holt JR. Can neurosphere production help restore inner ear transduction? Proc Natl Acad Sci U S A. 2009 Jan 6; 106(1):8-9.
  21. 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.
  22. 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 9; 432(7018):723-30.
  23. 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.
  24. Géléoc GS, Holt JR. Auditory amplification: outer hair cells pres the issue. Trends Neurosci. 2003 Mar; 26(3):115-7.
  25. 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.
  26. 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.
  27. 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 8; 108(3):371-81.
  28. 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.
  29. 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.
  30. Holt JR. Biology in pictures. A sense of colour. Curr Biol. 1999 May 20; 9(10):R351.
  31. 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.
  32. 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.
  33. Holt JR, Corey DP. Ion channel defects in hereditary hearing loss. Neuron. 1999 Feb; 22(2):217-9.
  34. 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.
  35. 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.
  36. 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.
  37. 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 8; 24(49):11148-59.
  38. 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.
  39. 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.
  40. 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.
  41. 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.
  42. 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.
  43. 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.
  44. 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.
  45. 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.
  46. 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.
  47. 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.
  48. 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 7; 79(3):504-15.
  49. 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.
  50. 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.
  51. 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 8; 12(10):1606-17.
  52. 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):115-23.
  53. Corey DP, Holt JR. Are TMCs the Mechanotransduction Channels of Vertebrate Hair Cells? J Neurosci. 2016 Oct 26; 36(43):10921-10926.
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Holt/Geleoc Laboratory

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F.M. Kirby Neurobiology Center

The F.M. Kirby Neurobiology Center, together with the Neurobiology Program at Boston Children’s Hospital, is the largest basic neuroscience research enterprise at a U.S. hospital. It incorporates basic and translational neuroscience research, focusing primarily on developmental neurobiology.

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