期刊
VISUAL NEUROSCIENCE
卷 24, 期 1, 页码 111-123出版社
CAMBRIDGE UNIV PRESS
DOI: 10.1017/S0952523807070149
关键词
chemical mutagenesis; forward genetics; retina; retinal ganglion cells; depolarizing bipolar cells; congenital stationary night blindness; ON pathway; molecular cloning; positional cloning; gene discovery; rod pathway; visual acuity
资金
- Howard Hughes Medical Institute Funding Source: Medline
- NEI NIH HHS [R01 EY006669, R01 EY06669, R01 EY014701, R01 EY012354] Funding Source: Medline
- NIMH NIH HHS [U01 MH061915-01A1, U01 MH061915-03, U01MH61915, U01 MH061915-05, U01 MH061915, U01 MH061915-04, U01 MH061915-02] Funding Source: Medline
- NATIONAL EYE INSTITUTE [R01EY014701, R01EY012354, R01EY006669] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [U01MH061915] Funding Source: NIH RePORTER
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 mGIuR6 did not display robust glutamate-induced currents. Retinal rnRNA levels for Grm6 were not significantly reduced, but no immunoreactivity for EnGluR6 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.
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