Primary research papers
Descriptions of results reported in selected recent papers is provided below
for a simple and broad overview of our most recent CRF-related work as it pertains to cochlear development and function, see:
http://f1000posters.com/PosterList?sectID=&specID=&posterID=708
(42 total, † journal cover illustration, ‡ cited > 100 times) Publishing metrics as of 7/31/14: h-index = 24; 8 manuscripts cited >100 times; i-10 index (# papers cited at least 10 times) = 31 (74%); i-50 index (number of papers with at least 50 citations) = 17 (40%); total citations = 3455 (last 5 years = 1146)
Clause, A., Kim, G., Sonntag, M., Weisz, C.J.C., Vetter, D.E., Rubsamen, R., and Kandler, K. (2014) The precise temporal pattern of pre-hearing spontaneous activity is necessary for tonotopic map refinement. Neuron 82(4):822-835.
This work describes the existence of a molecularly identical signaling system in the cochlea to the classic HPA axis. Additionally, it demonstrates the role of CRFR1 in hair cell development and innervation. CRFR1 null mice possess small inner hair cells. These cells are also abnormally innervated by the Type 1 spiral ganglion cells. Adult CRFR1 null mice also present with significant ABR threshold elevation (20-30dB).
Turcan, S., Vetter, D.E., Maron, J.L., Wei, X., and Slonim, D.K. (2011) Mining functionally relevant gene sets for analyzing physiologically novel clinical expression data. Pacific Symposium on Biocomputing 50-61.
Basappa, J.,
Turcan, S., and Vetter, D.E. (2010) CRF2
activation prevents gentamicin-induced oxidative stress in cells derived from
the inner ear. J. Neurosci. Res. 88(13):2976-90.
This work describes
biochemical evidence that the corticotropin releasing factor receptor 2
protects inner ear cells from damage resulting from exposure to aminoglycosides.
We show that generation of reactive oxygen species is dampened following
pre-activation of CRF receptor 2, and caspase 3 and superoxide dismutase
activation are held to baseline levels. We go on to use iTRAQ proteomic
techniques (LC-MS/MS) to define the expression level changes to the proteome.
Maison, S., Liu, X-P., Vetter, D.E., Eatock, R., Nathanson, N.M., Wess, J., and Liberman,
M.C. (2010) Muscarinic signaling in the cochlea: Presynaptic and post-synaptic
effects on efferent feedback and afferent excitability. J. Neurosci. 30:6751-6762.
Graham, C.E., Basappa, J., and Vetter, D.E. (2010) A corticotropin-releasing factor system expressed in the mammalian cochlea modulates hearing sensitivity and protects against noise-induced hearing loss. Neurobiol. Disease 38:246-258.
This work describes the role of CRF receptor 2 in cochlear function. Chief among the results was a significant lowering of the auditory brainstem response threshold of mice lacking the CRFR2 gene, and their greater susceptibility to noise-induced hearing loss. Additionally, we present data detailing expression levels of various proteins involved in afferent signal processing and show that ATP and glutamate receptor expression is abnormal in the CRFR2 null mice.
Turcan, S., Slonim, D.K., and Vetter, D.E. (2010) Lack of nAChR activity depresses cochlear maturation and up-regulates GABA system components: Temporal profiling of gene expression in a9 null mice. PLoS One, 5(2):e9058.
This work demonstrates gene expression changes over time during postnatal development (pre-hearing and early post-hearing stages) and in adult following loss of Chrna9 (alpha 9 nAChR) expression. Major findings include abnormal GABAergic receptor expression, linking ACh signaling to the GABA system of the cochlea for the first time. Using primary component analysis (PCA) of our gene expression arrays, we also show that the cochlea of alpha 9 null mice is developmentally retarded with respect to the global gene expression profile.
†Murthy, V., Taranda, J., Elgoyhen, A.B., and Vetter, D.E. (2009) Loss of activity through nAChRs containing the a9 subunit disrupts synapse stabilization and modulates expression of presynaptic release machinery via bidirectional signaling programs. Dev. Neurobiol. 69(14):931-949. (work highlighted by cover illustration)
This work demonstrates for the first time how activity through the hair cell nAChR complex alters protein expression and structure of both the efferent synaptic terminal (pre-synaptic element) and the afferent release machinery of hair cells. We use our data to develop a molecular model based on abnormal N-Cadherin expression and signaling to explain both cell signaling and synaptic structure defects found in the alpha 9 nAChR nulls, and describe a hyperinnervation of the efferent synapse onto outer hair cells following a point mutation to the alpha 9 gene resulting in hyperactive and exaggerated (non-desensitizing) nAChR currents. The hyerinneration of the point mutant is opposite the innervation phenotype of the null, which results in fewer, but hypertrophic, efferent terminals contacting outer hair cells.
Taranda, J., Ballestero, J., Hiel, H., de Souza, F.S.J., Gomez-Casati, M.E., Wedemeyer, C., Lipovsek, M., Savino, J., Rubenstein, M., Vetter, D.E., Fuchs, P.A., Katz, E., and Elgoyhen, A.B. (2009) Constitutive expression of the a10 nicotinic acetylcholine receptor subunit fails to maintain cholinergic responses in inner hair cells after the onset of hearing. J. Assoc. Res. Otolaryngol. 10(3):397-406.
Brown, M.C. and Vetter, D.E. (2009) Olivocochlear somata and branches are normal in a9 knockout mice. J. Assoc. Res. Otolaryngol. 10(1): 64-75.
This work was the product of an equal contribution between Dr. Brown and myself. Our data document the unexpected finding that collaterals to the cochlear nucleus originating from the medial olivocochlear system are normally distributed and possess normal appearing synaptic terminals. This stands in contrast to the condition of the terminals as they synapse with the outer hair cells, further demonstrating the importance of local feedback in determining the fate of synaptic structure.
Taranda, J, Maison, S, Ballestero, J, Katz, E , Savino, J, Vetter, DE, Boulter, J, Liberman, MC, Fuchs, PA, Elgoyhen, AB. (2009) A point mutation in the cochlear hair cell nicotinic acetylcholine receptor prolongs efferent inhibition to enhance noise protection. PLoS Biol. 7(1): e1000018 doi:10.1371/journal.pbio.1000018.
Murthy, V., Maison, S.F., Taranda, J., Haque, N., Bond, C.T., Elgoyhen, A.B., Adelman, J.P., Liberman, M.C., and Vetter D.E. (2009) SK2 channels are required for function and long-term survival of efferent synapses on mammalian outer hair cells. Mol. Cell. Neurosci. 40(1):39-49.
This work demonstrates the role of SK2 channels in olivocochlear development and function. The main findings of the work are that SK2 gene ablation results in a delayed but significant efferent terminal degeneration beginning just at the point of hearing onset. This stands in contrast to the hypertrophic terminals of the alpha 9 null and the hyper-innervation of the alpha 9 point mutant. We created an SK2/alpha 10 nAChR double null mouse to investigate epistatic interactions between these genes. Results indicate a gene hierarchy in which the SK2 phenotype dominates that of the alpha 10 phenotype.
Vetter, D.E., Basappa, J., and Turcan, S. (2009) Multiplexed isobaric tagging protocols for quantitative mass spectrometry approaches to auditory research. Methods Mol. Biol. 493:345-66.
Techniques and protocols paper in iTRAQ-based proteomics analyses for inner ear research.
Vetter D.E., Katz, E., Maison, S.F., Taranda, J., Turcan, S., Ballestero, J., Liberman, M.C. Elgoyhen, A.B., and Boulter, J. (2007) The a10 nicotinic acetylcholine receptor subunit is required for normal function and development of olivocochlear innervation. Proc. Nat. Acad. Sci., 104 (51): 20594-20599.
This work demonstrated the morphological and physiological consequences following genetic ablation of the Chrna 10 gene encoding the alpha 10 nAChR protein. The major results reported were that the structural phenotype is similar to, but not exactly the same as, that following ablation of Chrna9. Unexpectedly, we found a complete loss of nACh-inducible currents in hair cells, suggesting that alpha 9 homomers are not physiologically relevant. We show some evidence that such homomers do exist.
Chernyavskyy, A.I., Arredondo, J., Vetter, D.E., and Grando, S.A. (2007) Central role of alpha9 acetylcholine receptor in coordinating keratinocyte adhesion and motility at the initiation of epithelialization. Exp. Cell. Res. 2007 Oct 1; 313(16): 3542-55.
Maison S.F., Vetter D.E., Liberman M.C. (2007) A novel effect of cochlear efferents: in vivo response enhancement does not require a9 cholinergic receptors. J Neurophysiol. 97:3269-78.
Sage, C., Huang, M., Vollrath, M.A., Brown, M.C., Hinds, P.W., Corey, D.P., Vetter, D.E., and Chen, Z-Y., (2006) Essential role of retinoblastoma protein in mammalian hair cell development and hearing., Proc. Nat. Acad. Sci., 103:7345-7350.
Katz, E, Elgoyhen, A.B., Gómez-Casati, M.E., Knipper, M., Vetter, D.E., Fuchs, P.A., and Glowatzki, E. (2004) Developmental regulation of nicotinic synapses on cochlear inner hair cells. J. Neuroscience, 24: 7814-7820.
He, D.D.Z., Cheatum, M.A., Pearce, M., and Vetter, D.E. (2004) Mouse outer hair cells lacking the a9 ACh receptor are motile. Dev. Brain. Res.,148:19-25.
Nguyen, V-T, Chernyavsky, A.I., Arredondo, J., Bercovich, D., Orr-Urtreger, A., Vetter, D.E., Wess, J., Beaudet, A.L., Kitajima, Y., and Grando, S.A. (2004) Synergistic control of keratinocyte adhesion through muscarinic and nicotinic acetylcholine receptor subtypes. Exp. Cell Res. 294:534-549.
Arredondo, J., Nguyen, V-T., Chernyavsky, A.I., Bercovich, D., Orr-Urtreger, Vetter, D.E., and Grando. S.A. (2003) Functional role of a7 nicotinic receptor in physiological control of cutaneous homeostasis. Life Sciences, 72, 2063-2067.
‡ Arredondo, J., Nguyen, V-T, Chernyavsky, AI, Bercovich, D., Orr-Urtreger, A., Kummer, W., Lips, K., Vetter, D.E., and Grando, S.A. (2002) Central role of alpha7 nicotinic receptor in differentiation of the stratified squamous epithelium. J. Cell Biology, 159: 325-336.
‡ Vetter, D.E., Li, C., Zhou, L., Contarino, A., Liberman, M.C., Smith, G.W., Marchuk, Y., Koob, G.F., Heinemann, S.F., Vale, W., Lee, K-F. (2002) Urocortin-deficit mice display hearing impairments and increased anxiety-like activity. Nature Genetics, 31:363-369.
Weisstaub, N., Vetter, D.E., Elgoyhen, A.B., Katz, E. (2002) The a9a10 nicotinic acetylcholine receptor is permeable to and is modulated by divalent cations. Hearing Res., 167:122-35.
May, B.J., Prosen, C.A., Weiss, D., and Vetter, D.E. (2002) Behavioral investigation of some possible effects of the central olivocochlear pathways in transgenic mice. Hearing Res., 171:143-58.
‡ Elgoyhen, A.B., Vetter, D.E., Katz, E., Rothlin, C.R., Heinemann, S.F., and Boulter, J. (2001) a10: A determinant of nicotinic cholinergic receptor function in mammalian vestibular and cochlear mechanosensory hair cells. Proc. Nat. Acad. Sci., 98: 3501-3506.
Rothlin, C.V., Katz, E., Verbitsky, M., Vetter, D.E., Heinemann, S.F., Elgoyhen, A.B. (2000) Block of the a9 nicotinic receptor by ototoxic aminoglycosides. Neuropharmacology 39:2525-2532.
Prosen, C.A., Bath, K.G., Vetter, D.E., May, B.J. (2000) Behavioral assessments of auditory sensitivity in transgenic mice. J. Neurosci. Methods 97: 59-67.
Katz, E., Verbitsky, M., Rothlin, C.V., Vetter, D.E., Heinemann, S.F., and Elgoyhen, A.B. (2000) High calcium permeability and calcium block of the a9 nicotinic acetylcholine receptor. Hearing Research 141:117-128.
‡ Vetter, D.E., Liberman, M.C., Mann, J.R., Brown, M.C., Boulter, J., Barhanin, J., Saffiote, J., Heinemann, S.F., and Elgoyhen, A.B. (1999) Role of a9 nicotinic receptor subunits in the development and function of cochlear efferent innervation. Neuron 23:93-103.
Somia, N.V., Schmitt, M.J., Vetter, D.E., van Antwerp, D., Heinemann, S.F., and Verma, I.M. (1999) LFG: A novel anti-apoptotic gene that protects from Fas mediated cell death. Proc. Natl. Acad. Sci. 96:12667-12672.
‡ Vetter, D.E., Mann, J.R., Wangemann, P., Liu, J., McLaughlin, K.J., Lesage, F., Marcus, D.C., Lazdunski, M., Heinemann, S.F., and Barhanin, J. (1996) Inner ear defects induced by null mutation of the isk gene. Neuron 17: 1251-1264.
‡ Elgoyhen, A.B., Johnson, D.S., Boulter, J., Vetter, D.E., and Heinemann, S.F. (1994) a9: An acetylcholine receptor with novel pharmacological properties expressed in rat cochlear hair cells. Cell 79:705-715.
‡ Brose, N., Gasic, G., Vetter, D.E., and Heinemann, S.F. (1993) Protein chemical characterization and immunocytochemical localization of the NMDA receptor subunit NMDA R1. J. Biol. Chem. 268: 22663-22671.
Vetter, D.E., Saldaña E., and Mugnaini, E. (1993) Descending input from the central nucleus of the inferior colliculus to the medial olivocochlear system- A double label study with CT-B subunit and PHA-L. Hearing Res. 70: 173-196.
Vetter, D.E. and Mugnaini, E. (1992) Distribution and dendritic features of three groups of rat olivocochlear neurons: A study with two retrograde cholera toxin tracers. Anatomy and Embryology 185: 1-16.
‡ Vetter, D.E., Adams, J.C., and Mugnaini, E. (1991) Chemically distinct rat olivocochlear neurons. Synapse 7: 21-43.
Vetter, D.E. and Mugnaini, E. (1990) An evaluation of retrograde tracing methods for the identification of chemically distinct cochlear efferent neurons. Archives Italiennes de Biologie, 128: 331-353.
book chapters
Dunn, M.E., Vetter, D.E., Berrebi, A.S., Krider, H.M., and Mugnaini, E.
The mossy fiber-granule cell-cartwheel cell system in the mammalian cochlear nuclear complex. In: Advances in Speech Hearing and Language Processing, Volume III, part A. Cochlear Nucleus: Structure and Function in relation to Modeling. W.A. Ainsworth, E.F. Evans, and C.M. Hackney, eds. JAI Press Ltd, London. pp 63-87. 1996.
Vetter, D.E., Cozzari, C., Hartmann, B.K., Mugnaini, E.
Choline acetyltransferase in the rat cochlear nuclei: Light and electron microscopic immunolocalization with a monoclonal antibody. In: The Mammalian Cochlear Nuclei: Organization and Function. M. Merchan, J. Juiz, D. Godfrey, and E. Mugnaini eds. Plenum Press, New York. pp 279-290. 1993.