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Generation, identification and functional characterization of the nob4 mutation of Grm6 in the mouse

Published online by Cambridge University Press:  12 April 2007

LAWRENCE H. PINTO ,
MARTHA H. VITATERNA ,
KAZUHIRO SHIMOMURA ,
SANDRA M. SIEPKA ,
VICTORIA BALANNIK ,
ERIN L. MCDEARMON ,
CHIAKI OMURA ,
STEPHEN LUMAYAG ,
BRANDON M. INVERGO  and
BRETT GLAWE
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LAWRENCE H. PINTO
Affiliation:
Department of Neurobiology and Physiology and Center for Functional Genomics, Northwestern University, Evanston, Illinois
MARTHA H. VITATERNA
Affiliation:
Department of Neurobiology and Physiology and Center for Functional Genomics, Northwestern University, Evanston, Illinois
KAZUHIRO SHIMOMURA
Affiliation:
Department of Neurobiology and Physiology and Center for Functional Genomics, Northwestern University, Evanston, Illinois
SANDRA M. SIEPKA
Affiliation:
Department of Neurobiology and Physiology and Center for Functional Genomics, Northwestern University, Evanston, Illinois
VICTORIA BALANNIK
Affiliation:
Department of Neurobiology and Physiology and Center for Functional Genomics, Northwestern University, Evanston, Illinois
ERIN L. MCDEARMON
Affiliation:
Department of Neurobiology and Physiology and Center for Functional Genomics, Northwestern University, Evanston, Illinois Howard Hughes Medical Institute, Northwestern University, Evanston, Illinois
CHIAKI OMURA
Affiliation:
Department of Neurobiology and Physiology and Center for Functional Genomics, Northwestern University, Evanston, Illinois
STEPHEN LUMAYAG
Affiliation:
Department of Neurobiology and Physiology and Center for Functional Genomics, Northwestern University, Evanston, Illinois
BRANDON M. INVERGO
Affiliation:
Department of Neurobiology and Physiology and Center for Functional Genomics, Northwestern University, Evanston, Illinois
BRETT GLAWE
Affiliation:
Department of Neurobiology and Physiology and Center for Functional Genomics, Northwestern University, Evanston, Illinois
DONALD R. CANTRELL
Affiliation:
Department of Biomedical Engineering, McCormick School of Engineering Northwestern University, Evanston, Illinois
SAMSOON INAYAT
Affiliation:
Department of Biomedical Engineering, McCormick School of Engineering Northwestern University, Evanston, Illinois Department of Mechatronics and Control Engineering, University of Engineering and Technology, Lahore, Pakistan
MARISSA A. OLVERA
Affiliation:
Department of Ophthalmology & Visual Sciences, University of Iowa, Iowa City, Iowa
KIRSTAN A. VESSEY
Affiliation:
Department of Psychological and Brain Sciences, University of Louisville, Louisville, Kentucky
MAUREEN A. McCALL
Affiliation:
Department of Psychological and Brain Sciences, University of Louisville, Louisville, Kentucky Department of Ophthalmology & Visual Sciences, University of Louisville, Louisville, Kentucky
DENNIS MADDOX
Affiliation:
The Jackson Laboratory, Bar Harbor, Maine
CATHERINE W. MORGANS
Affiliation:
Neurological Sciences Institute, Oregon Health and Science University, Beaverton, Oregon
BRANDON YOUNG
Affiliation:
The Scripps Research Institute, Jupiter, Florida
MATHEW T. PLETCHER
Affiliation:
The Scripps Research Institute, Jupiter, Florida
ROBERT F. MULLINS
Affiliation:
Department of Ophthalmology & Visual Sciences, University of Iowa, Iowa City, Iowa
JOHN B. TROY
Affiliation:
Department of Biomedical Engineering, McCormick School of Engineering Northwestern University, Evanston, Illinois
JOSEPH S. TAKAHASHI
Affiliation:
Department of Neurobiology and Physiology and Center for Functional Genomics, Northwestern University, Evanston, Illinois Howard Hughes Medical Institute, Northwestern University, Evanston, Illinois
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Abstract

We performed genome-wide chemical mutagenesis of C57BL/6J mice using N-ethyl-N-nitrosourea (ENU). Electroretinographic screening of the third generation offspring revealed two G3 individuals from one G1 family with a normal a-wave but lacking the b-wave that we named nob4. The mutation was transmitted with a recessive mode of inheritance and mapped to chromosome 11 in a region containing the Grm6 gene, which encodes a metabotropic glutamate receptor protein, mGluR6. Sequencing confirmed a single nucleotide substitution from T to C in the Grm6 gene. The mutation is predicted to result in substitution of Pro for Ser at position 185 within the extracellular, ligand-binding domain and oocytes expressing the homologous mutation in mGluR6 did not display robust glutamate-induced currents. Retinal mRNA levels for Grm6 were not significantly reduced, but no immunoreactivity for mGluR6 protein was found. Histological and fundus evaluations of nob4 showed normal retinal morphology. In contrast, the mutation has severe consequences for visual function. In nob4 mice, fewer retinal ganglion cells (RGCs) responded to the onset (ON) of a bright full field stimulus. When ON responses could be evoked, their onset was significantly delayed. Visual acuity and contrast sensitivity, measured with optomotor responses, were reduced under both photopic and scotopic conditions. This mutant will be useful because its phenotype is similar to that of human patients with congenital stationary night blindness and will provide a tool for understanding retinal circuitry and the role of ganglion cell encoding of visual information.

Keywords

Chemical mutagenesisForward geneticsRetinaRetinal ganglion cellsDepolarizing bipolar cellsCongenital stationary night blindnessON pathwayMolecular cloningPositional cloningGene discoveryRod pathwayVisual acuity
Type
Research Article
Information
Visual Neuroscience , Volume 24 , Issue 1 , January 2007 , pp. 111 - 123
Copyright
© 2007 Cambridge University Press

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References

REFERENCES

Chang, B., Heckenlively, J.R., Bayley, P.R., Brecha, N.C., Davisson, M.T., Hawes, N.L., Hirano, A.A., Hurd, R.E., Ikeda, A., Johnson, B.A., McCall, M.A., Morgans, C.W., Nusinowitz, S., Peachey, N.S., Rice, D.S., Vessey, K.A. & Gregg, R.G. (2006). The nob2 mouse, a null mutation in Cacna1f: Anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses. Visual Neuroscience 23, 11–24.CrossRefGoogle Scholar
Dawson, W.W., Trick, G.L. & Litzkow, C.A. (1979). Improved electrode for electroretinography. Investigative Ophthalmology & Visual Science 18, 988–991.Google Scholar
Dryja, T.P., McGee, T.L., Berson, E.L., Fishman, G.A., Sandberg, M.A., Alexander, K.R., Derlacki, D.J. & Rajagopalan, A.S. (2005). Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6. Proceedings of the National Academy of Science USA 102, 4884–4889.CrossRefGoogle Scholar
Gregg, R.G., Mukhopadhyay, S., Candille, S.I., Ball, S.L., Pardue, M.T., McCall, M.A. & Peachey, N.S. (2003). Identification of the gene and the mutation responsible for the mouse nob phenotype. Investigative Ophthalmology & Visual Science 44, 378–384.CrossRefGoogle Scholar
Kuffler, S.W. (1953). Discharge patterns and functional organization of mammalian retina. Journal of Neurophysiology 16, 37–68.Google Scholar
Kunishima, N., Shimada, Y., Tsuji, Y., Sato, T., Yamamoto, M., Kumasaka, T., Nakanishi, S., Jingami, H. & Morikawa, K. (2000). Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 407, 971–977.Google Scholar
Masu, M., Iwakabe, H., Tagawa, Y., Miyoshi, T., Yamashita, M., Fukuda, Y., Sasaki, H., Hiroi, K., Nakamura, Y., Shigemoto, R., Takada, M., Nakamura, K., Nakao, K., Katsuki, M. & Nakanishi, S. (1995). Specific deficit of the ON response in visual transmission by targeted disruption of the mGluR6 gene. Cell 80, 757–765.CrossRefGoogle Scholar
McGill, T.J., Douglas, R.M., Lund, R.D. & Prusky, G.T. (2004). Quantification of spatial vision in the Royal College of Surgeons rat. Investigative Ophthalmology & Visual Science 45, 932–936.CrossRefGoogle Scholar
Morgans, C.W., Bayley, P.R., Oesch, N.W., Ren, G., Akileswaran, L. & Taylor, W.R. (2005). Photoreceptor calcium channels: Insight from night blindness. Visual Neuroscience 22, 561–568.CrossRefGoogle Scholar
Morgans, C.W., Ren, G. & Akileswaran, L. (2006). Localization of nyctalopin in the mammalian retina. European Journal of Neuroscience 23, 1163–1171.CrossRefGoogle Scholar
Nirenberg, S., Carcieri, S.M., Jacobs, A.L. & Latham, P.E. (2001). Retinal ganglion cells act largely as independent encoders. Nature 411, 698–701.CrossRefGoogle Scholar
Nirenberg, S. & Meister, M. (1997). The light response of retinal ganglion cells is truncated by a displaced amacrine circuit. Neuron 18, 637–650.CrossRefGoogle Scholar
O'Connor, E., Allen, L.E., Bradshaw, K., Boylan, J., Moore, A.T. & Trump, D. (2006). Congenital stationary night blindness associated with mutations in GRM6 encoding glutamate receptor MGluR6. British Journal of Ophthalmology 90, 653–654.CrossRefGoogle Scholar
Pardue, M.T., McCall, M.A., LaVail, M.M., Gregg, R.G. & Peachey, N.S. (1998). A naturally occurring mouse model of X-linked congenital stationary night blindness. Investigative Ophthalmology & Visual Science 39, 2443–2449.Google Scholar
Pinto, L.H., Vitaterna, M.H., Shimomura, K., Siepka, S.M., McDearmon, E.L., Fenner, D., Lumayag, S.L., Omura, C., Andrews, A.W., Baker, M., Invergo, B.M., Olvera, M.A., Heffron, E., Mullins, R.F., Sheffield, V.C., Stone, E.M. & Takahashi, J.S. (2005). Generation, characterization, and molecular cloning of the Noerg-1 mutation of rhodopsin in the mouse. Visual Neuroscience 22, 619–629.CrossRefGoogle Scholar
Pinto, L.H., Vitaterna, M.H., Siepka, S.M., Shimomura, K., Lumayag, S., Baker, M., Fenner, D., Mullins, R.F., Sheffield, V.C., Stone, E.M., Heffron, E. & Takahashi, J.S. (2004). Results from screening over 9000 mutation-bearing mice for defects in the electroretinogram and appearance of the fundus. Vision Research 44, 3335–3345.CrossRefGoogle Scholar
Renteria, R.C., Tian, N., Cang, J., Nakanishi, S., Stryker, M. & Copenhagen, M. (2006). Intrinsic ON responses of the retinal OFF pathway are suppressed by the ON pathway. Journal of Neuroscience 26, 11857–11869Google Scholar
Rosemond, E., Wang, M., Yao, Y., Storjohann, L., Stormann, T., Johnson, E.C. & Hampson, D.R. (2004). Molecular basis for the differential agonist affinities of group III metabotropic glutamate receptors. Molecular Pharmacology 66, 834–842.CrossRefGoogle Scholar
Sagdullaev, B.T. & McCall, M.A. (2005). Stimulus size and intensity alter fundamental receptive-field properties of mouse retinal ganglion cells in vivo. Visual Neuroscience 22, 649–659.CrossRefGoogle Scholar
Saszik, S.M., Robson, J.G. & Frishman, L.J. (2002). The scotopic threshold response of the dark-adapted electroretinogram of the mouse. The Journal of Physiology 543, 899–916.Google Scholar
Sharon, D., Vorobiov, D. & Dascal, N. (1997). Positive and negative coupling of the metabotropic glutamate receptors to a G protein-activated K+ channel, GIRK, in Xenopus oocytes. The Journal of General Physiology 109, 477–490.CrossRefGoogle Scholar
Shimbo, K., Brassard, D.L., Lamb, R.A. & Pinto, L.H. (1996). Ion selectivity and activation of the M2 ion channel of influenza virus. Biophysical Journal 70, 1335–1346.CrossRefGoogle Scholar
Siepka, S.M. & Takahashi, J.S. (2005). Forward genetic screen to identify circadian rhythm mutants in mice. Methods in Enzymology 393, 217–228.Google Scholar
Slaughter, M.M. & Miller, R.F. (1981). 2-amino-4-phosphonobutyric acid: a new pharmacological tool for retina research. Science 211, 182–185.CrossRefGoogle Scholar
Stern-Bach, Y., Bettler, B., Hartley, M., Sheppard, P.O., O'Hara, P.J. & Heinemann, S.F. (1994). Agonist selectivity of glutamate receptors is specified by two domains structurally related to bacterial amino acid-binding proteins. Neuron 13, 1345–1357.CrossRefGoogle Scholar
Vitaterna, M.H., Pinto, L.H. & Takahashi, J.S. (2006). Large-scale mutagenesis and phenotypic screens for the nervous system and behavior in mice. Trends in Neuroscience 29, 233–240.CrossRefGoogle Scholar
Zeitz, C., van Genderen, M., Neidhardt, J., Luhmann, U.F., Hoeben, F., Forster, U., Wycisk, K., Matyas, G., Hoyng, C.B., Riemslag, F., Meire, F., Cremers, F.P. & Berger, W. (2005). Mutations in GRM6 cause autosomal recessive congenital stationary night blindness with a distinctive scotopic 15-Hz flicker electroretinogram. Investigative Ophthalmology & Visual Science 46, 4328–4335.CrossRefGoogle Scholar