Jeffrey R. Holt, Ph.D.
Associate Professor
Departments of Neuroscience and Otolaryngology


Ph.D., 1995, University of Rochester
1995-1999  Postdoctoral Fellow, Massachusetts General Hospital and Harvard Medical School
1999-2001  Instructor in Neurobiology, Harvard Medical School, Boston, MA

Molecular Physiology of Hearing and Balance

Elegant models for mechanoelectrical transduction and sensory processing in the ear have evolved out of the systematic, biophysical characterization of hair cells from amphibians, reptiles and birds over the last quarter century.  Building on these observations, we now turn toward a more molecular approach that offers the promise of identification and characterization of a cast of hypothesized players.

Sensory hair cells in the epithelia of the mouse inner ear present a robust opportunity for convergence of the biophysical and molecular domains.  We have refined an in vitro preparation of the auditory and vestibular epithelia for the physiologic study of transgenic animals and for acute introduction of exogenous genes.  Both approaches have already yielded some exciting results.  1) Using a transgenic approach my collaborators and I have recently demonstrated that a motor protein (the unconventional myosin, Myo1c) participates in sensory adaptation in vestibular hair cells.  2) Using adenoviral vectors, we have demonstrated that viral-based, gene-transfer can mediate functional expression of exogenous genes in hair cells.  With either technology we can introduce exogenous gene constructs to manipulate endogenous gene and protein activity.  Subsequent assays for functional disruption can link a molecular identity with its physiologic correlate and offer insight into gene and protein function.  We are currently using these approaches to investigate the role of myosin motor proteins and ion channel proteins in the generation and modulation of the sensory signal in mammalian hair cells.  Our long term goal is to identify and characterize genes and proteins involved in normal function and in dysfunction of the auditory and vestibular systems.  

Figure1. Transduction currents from a wild-type mouse and a transgenic mouse. The current decay in the control trace (black) illustrates wild-type adaptation. Adaptation in the transgenic mouse (red trace) has been blocked by the mutant Myo1c protein.


 

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Figure 2. Proof of principal experiments demonstrating adenoviral-mediated expression of the exogenous gene, green fluorescent protein, in hair cells. A. Cross-section of a single hair cell from a mouse vestibular organ. B. Several hair cells from the mouse auditory organ viewed from above.

 

 

 

 

 

 

 
 

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  Representative Publications

  • J.R. Risner J.R. and J.R. Holt.  (2006)  Heterogeneous potassium conductances contribute to the diverse firing properties of postnatal mouse vestibular ganglion neurons. J Neurophysiol. 96(5):2364-76.
  • E.A. Stauffer, J. Scarborough, M. Hirono, E.D. Miller, K. Shah, J.A. Mercer, J. R. Holt, and P. G. Gillespie. (2005) Fast Adaptation in Vestibular Hair Cells Requires Myosin-1c Activity. Neuron. 47:541-553.
  • G.S.G. Géléoc, J.R. Risner and J.R. Holt. (2004) Developmental acquisition of voltage-dependent conductances and sensory signaling in hair cells of the embryonic mouse inner ear. J. Neurosci. 24:11148-11159.  
  • D.P. Corey,J. García-Añoveros, J. R. Holt, K.Y. Kwan, S-Y. Lin, M. A. Vollrath, A. Amalfitano, E. L-M. Cheung, B. H. Derfler, A. Duggan, G.S.G. Géléoc, P.A. Gray, M.P. Hoffman, H.L. Rehm, D. Tamasauskas, D-S. Zhang. (2004) TRPA1 is a candidate for the mehcanosensitive transduction channel of vertebrate hair cells. Nature 432:723-730
  • G.S.G. Géléoc and J.R. Holt. (2003) Developmental acquisition of sensory transduction in hair cells of the mouse inner ear.  Nature Neuroscience 6(10), 1019-20.
  • J. R. Holt,  S. K. H. Gillespie, D. W. Provance, Jr.,  K.Shah,  K. M. Shokat,  D. P. Corey, J. A. Mercer, and P. G. Gillespie. (2002)  A chemical-genetic strategy implicates myosin 1c in adaptation by hair cells.  Cell 108, 371-381, 2002.
  • J.R. Holt and D.P. Corey.  (2000) Two mechanisms for transducer adaptation in vertebrate hair cells.  PNAS 97, 11730-11735. 2000.
  • J.R. Holt, D.C. Johns, S. Wang, Z.Y. Chen, E. Marban and DP Corey. (1999) Functional expression of exogenous proteins in mammalian sensory hair cells infected with adenoviral vectors.  J.Neurophysiology, 81, 1881-1888.
  • J.R. Holt and DP Corey. (1999) Ion Channel Defects in Hereditary Hearing Loss.  Neuron, 22, 217-219.
  • J.S. Oghalai, J.R. Holt, T. Nakagawa, T.M. Jung, N. J. Coker, H.A. Jenkins, R.A. Eatock, W.E. Brownell.  (1998) Ionic currents and electromotility in human hair cells. J. Neurophysiol  79, 2235-9.
  • J.R. Holt, DP Corey, R.A. Eatock,  (1997) Mechanoelectrical transduction and adaptation in hair cells of the mouse utricle, a low-frequency vestibular organ.  J. Neuroscience, 17:22, pp8739-8748.
  • W. Denk, J.R. Holt, G.M.G. Shepperd, DP Corey.  (1995) Calcium imaging of single stereocilia in hair cells:  Localization of transduction channels at both ends of tip links.  Neuron, 15 pp1311-21.
  • J.R. Holt and R.A. Eatock. (1995)  Inwardly rectifying currents of saccular hair cells from the leopard frog.  J. Neurophysiology, 73:4 pp1484-1502.

Lab Web Site


 

E-mail: jeffholt@virginia.edu
MR-4 Room 5126
(434) 243-9995