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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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