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Imaging Ca2+ Dynamics in Cone Photoreceptor Axon Terminals of the Mouse Retina
Published on: May 6, 2015
Photoreceptor degeneration, azoospermia, leukoencephalopathy, and abnormal RPE cell function in mice expressing an
Malia M Edwards1, Caralina Marín de Evsikova, Gayle B Collin
1Jackson Laboratory, Bar Harbor, Maine, USA. medwar28@jhmi.edu
Purpose:
To determine the molecular basis and the pathologic consequences of a chemically induced mutation in a mouse model of photoreceptor degeneration, nmf240.
Methods:
Mice from a G3 N-ethyl-N-nitrosourea mutagenesis program were screened by indirect ophthalmoscopy for abnormal fundi. A chromosomal position for the recessive nmf240 mutation was determined by a genome-wide linkage analysis by use of simple sequence length polymorphic markers in an F2 intercross. The critical region was refined, and candidate genes were screened by direct sequencing. The nmf240 phenotype was characterized by histologic analysis of the retina, brain, and male reproductive organs and by electroretinogram (ERG)-based studies of the retina and retinal pigment epithelium (RPE).
Results:
Clinically, homozygous nmf240 mutants exhibit a grainy retina that progresses to panretinal patches of depigmentation. The mutation was localized to a region on chromosome 16 containing Clcn2, a gene associated with retinal degeneration. Sequencing identified a missense C-T mutation at nucleotide 1063 in Clcn2 that converts a glutamine to a stop codon. Mice homozygous for the Clcn2(nmf240) mutation experience a severe loss of photoreceptor cells at 14 days of age that is preceded by an elongation of RPE apical microvilli. Homozygous mutants also experience leukoencephalopathy in multiple brain areas and male sterility. Despite a normal retinal histology in nmf240 heterozygotes, the ERG light peak, generated by the RPE, is reduced.
Conclusions:
The nmf240 phenotype closely resembles that reported for Clcn2 knockout mice. The observation that heterozygous nmf240 mice present with a reduced ERG light peak component suggests that CLCN2 is necessary for the generation of this response component.
Insights
A chemically induced mutation in the Clcn2 gene causes photoreceptor degeneration and leukoencephalopathy in mice. This study identifies the molecular basis and pathological consequences of this mutation.
Area of Science:
- Genetics
- Neuroscience
- Ophthalmology
Background:
- Photoreceptor degeneration leads to vision loss.
- Mouse models are crucial for understanding retinal diseases.
- Chemical mutagenesis screens identify novel genetic mutations.
Purpose of the Study:
- To elucidate the molecular basis of the nmf240 mutation.
- To characterize the pathological consequences of this mutation in a mouse model.
- To investigate the role of CLCN2 in retinal function.
Main Methods:
- N-ethyl-N-nitrosourea mutagenesis and screening for retinal abnormalities.
- Genome-wide linkage analysis to map the mutation.
- Histological analysis of retina, brain, and reproductive organs.
- Electroretinogram (ERG) studies to assess retinal function.
Main Results:
- A missense mutation in the Clcn2 gene was identified as the cause of the nmf240 phenotype.
- Homozygous mutants exhibited severe photoreceptor loss, leukoencephalopathy, and male sterility.
- Heterozygous mice showed a reduced ERG light peak, suggesting CLCN2's role in RPE function.
Conclusions:
- The nmf240 mutation in Clcn2 causes a phenotype similar to Clcn2 knockout mice.
- CLCN2 is essential for normal photoreceptor function and RPE activity.
- This mouse model provides insights into Clcn2-related retinal degeneration.
