Limits...
Variable phenotypic expressivity in inbred retinal degeneration mouse lines: A comparative study of C3H/HeOu and FVB/N rd1 mice.

van Wyk M, Schneider S, Kleinlogel S - Mol. Vis. (2015)

Bottom Line: Recent advances in optogenetics and gene therapy have led to promising new treatment strategies for blindness caused by retinal photoreceptor loss.The rd1 founder mutation is present in more than 100 actively used mouse lines.By postnatal week 4, the FVB/N mice expressed significantly less cone opsin and Pde6b mRNA and had neither ERG nor OKR responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of Bern, Bern, Switzerland.

ABSTRACT

Purpose: Recent advances in optogenetics and gene therapy have led to promising new treatment strategies for blindness caused by retinal photoreceptor loss. Preclinical studies often rely on the retinal degeneration 1 (rd1 or Pde6b(rd1)) retinitis pigmentosa (RP) mouse model. The rd1 founder mutation is present in more than 100 actively used mouse lines. Since secondary genetic traits are well-known to modify the phenotypic progression of photoreceptor degeneration in animal models and human patients with RP, negligence of the genetic background in the rd1 mouse model is unwarranted. Moreover, the success of various potential therapies, including optogenetic gene therapy and prosthetic implants, depends on the progress of retinal degeneration, which might differ between rd1 mice. To examine the prospect of phenotypic expressivity in the rd1 mouse model, we compared the progress of retinal degeneration in two common rd1 lines, C3H/HeOu and FVB/N.

Methods: We followed retinal degeneration over 24 weeks in FVB/N, C3H/HeOu, and congenic Pde6b(+) seeing mouse lines, using a range of experimental techniques including extracellular recordings from retinal ganglion cells, PCR quantification of cone opsin and Pde6b transcripts, in vivo flash electroretinogram (ERG), and behavioral optokinetic reflex (OKR) recordings.

Results: We demonstrated a substantial difference in the speed of retinal degeneration and accompanying loss of visual function between the two rd1 lines. Photoreceptor degeneration and loss of vision were faster with an earlier onset in the FVB/N mice compared to C3H/HeOu mice, whereas the performance of the Pde6b(+) mice did not differ significantly in any of the tests. By postnatal week 4, the FVB/N mice expressed significantly less cone opsin and Pde6b mRNA and had neither ERG nor OKR responses. At 12 weeks of age, the retinal ganglion cells of the FVB/N mice had lost all light responses. In contrast, 4-week-old C3H/HeOu mice still had ERG and OKR responses, and we still recorded light responses from C3H/HeOu retinal ganglion cells until the age of 24 weeks. These results show that genetic background plays an important role in the rd1 mouse pathology.

Conclusions: Analogous to human RP, the mouse genetic background strongly influences the rd1 phenotype. Thus, different rd1 mouse lines may follow different timelines of retinal degeneration, making exact knowledge of genetic background imperative in all studies that use rd1 models.

No MeSH data available.


Related in: MedlinePlus

Maximum spatial acuity of the optokinetic reflex (OKR) responses. Although both Pde6b+ mouse lines responded to spatial frequencies characteristic of wild-type mice with no significant difference between the two mouse lines, only young 4-week-old C3H/HeOu mice reliably responded with a tracking reflex and only to relatively low spatial frequencies (0.062±0.02 cyc/deg). The number of C3H/HeOu mice with an OKR response decreased steadily with age and approached zero at 24 weeks. The FVB/N mice did not have a detectable OKR at any age. The fit is exponential with an R-square value of 0.92.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4522243&req=5

f7: Maximum spatial acuity of the optokinetic reflex (OKR) responses. Although both Pde6b+ mouse lines responded to spatial frequencies characteristic of wild-type mice with no significant difference between the two mouse lines, only young 4-week-old C3H/HeOu mice reliably responded with a tracking reflex and only to relatively low spatial frequencies (0.062±0.02 cyc/deg). The number of C3H/HeOu mice with an OKR response decreased steadily with age and approached zero at 24 weeks. The FVB/N mice did not have a detectable OKR at any age. The fit is exponential with an R-square value of 0.92.

Mentions: To go beyond the retina, we behaviorally probed for the integrity of the visual reflex circuitry by testing the maximum spatial frequency able to trigger an optokinetic reflex (OKR). Again, the performances of the seeing FVB-Pde6b+ and C3H-Pde6b+ mice were similar with maximum spatial frequencies of 0.359±0.037 cyc/deg and 0.366±0.011 cyc/deg, respectively, corresponding closely to that of C57/BL6 mice [51]. In line with the ERG results, the 4-week-old C3H/HeOu mice responded to the moving grating, but only to the spatial frequency perceived best by mice (0.062±0.026 cyc/deg). The number of C3H/HeOu mice with a tracking reflex steadily declined with age until no mice responded at 24 weeks (Figure 7). Equal to the ERG experiments, we were not able to measure an OKR response at any time point in the FVB/N mice.


Variable phenotypic expressivity in inbred retinal degeneration mouse lines: A comparative study of C3H/HeOu and FVB/N rd1 mice.

van Wyk M, Schneider S, Kleinlogel S - Mol. Vis. (2015)

Maximum spatial acuity of the optokinetic reflex (OKR) responses. Although both Pde6b+ mouse lines responded to spatial frequencies characteristic of wild-type mice with no significant difference between the two mouse lines, only young 4-week-old C3H/HeOu mice reliably responded with a tracking reflex and only to relatively low spatial frequencies (0.062±0.02 cyc/deg). The number of C3H/HeOu mice with an OKR response decreased steadily with age and approached zero at 24 weeks. The FVB/N mice did not have a detectable OKR at any age. The fit is exponential with an R-square value of 0.92.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4522243&req=5

f7: Maximum spatial acuity of the optokinetic reflex (OKR) responses. Although both Pde6b+ mouse lines responded to spatial frequencies characteristic of wild-type mice with no significant difference between the two mouse lines, only young 4-week-old C3H/HeOu mice reliably responded with a tracking reflex and only to relatively low spatial frequencies (0.062±0.02 cyc/deg). The number of C3H/HeOu mice with an OKR response decreased steadily with age and approached zero at 24 weeks. The FVB/N mice did not have a detectable OKR at any age. The fit is exponential with an R-square value of 0.92.
Mentions: To go beyond the retina, we behaviorally probed for the integrity of the visual reflex circuitry by testing the maximum spatial frequency able to trigger an optokinetic reflex (OKR). Again, the performances of the seeing FVB-Pde6b+ and C3H-Pde6b+ mice were similar with maximum spatial frequencies of 0.359±0.037 cyc/deg and 0.366±0.011 cyc/deg, respectively, corresponding closely to that of C57/BL6 mice [51]. In line with the ERG results, the 4-week-old C3H/HeOu mice responded to the moving grating, but only to the spatial frequency perceived best by mice (0.062±0.026 cyc/deg). The number of C3H/HeOu mice with a tracking reflex steadily declined with age until no mice responded at 24 weeks (Figure 7). Equal to the ERG experiments, we were not able to measure an OKR response at any time point in the FVB/N mice.

Bottom Line: Recent advances in optogenetics and gene therapy have led to promising new treatment strategies for blindness caused by retinal photoreceptor loss.The rd1 founder mutation is present in more than 100 actively used mouse lines.By postnatal week 4, the FVB/N mice expressed significantly less cone opsin and Pde6b mRNA and had neither ERG nor OKR responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of Bern, Bern, Switzerland.

ABSTRACT

Purpose: Recent advances in optogenetics and gene therapy have led to promising new treatment strategies for blindness caused by retinal photoreceptor loss. Preclinical studies often rely on the retinal degeneration 1 (rd1 or Pde6b(rd1)) retinitis pigmentosa (RP) mouse model. The rd1 founder mutation is present in more than 100 actively used mouse lines. Since secondary genetic traits are well-known to modify the phenotypic progression of photoreceptor degeneration in animal models and human patients with RP, negligence of the genetic background in the rd1 mouse model is unwarranted. Moreover, the success of various potential therapies, including optogenetic gene therapy and prosthetic implants, depends on the progress of retinal degeneration, which might differ between rd1 mice. To examine the prospect of phenotypic expressivity in the rd1 mouse model, we compared the progress of retinal degeneration in two common rd1 lines, C3H/HeOu and FVB/N.

Methods: We followed retinal degeneration over 24 weeks in FVB/N, C3H/HeOu, and congenic Pde6b(+) seeing mouse lines, using a range of experimental techniques including extracellular recordings from retinal ganglion cells, PCR quantification of cone opsin and Pde6b transcripts, in vivo flash electroretinogram (ERG), and behavioral optokinetic reflex (OKR) recordings.

Results: We demonstrated a substantial difference in the speed of retinal degeneration and accompanying loss of visual function between the two rd1 lines. Photoreceptor degeneration and loss of vision were faster with an earlier onset in the FVB/N mice compared to C3H/HeOu mice, whereas the performance of the Pde6b(+) mice did not differ significantly in any of the tests. By postnatal week 4, the FVB/N mice expressed significantly less cone opsin and Pde6b mRNA and had neither ERG nor OKR responses. At 12 weeks of age, the retinal ganglion cells of the FVB/N mice had lost all light responses. In contrast, 4-week-old C3H/HeOu mice still had ERG and OKR responses, and we still recorded light responses from C3H/HeOu retinal ganglion cells until the age of 24 weeks. These results show that genetic background plays an important role in the rd1 mouse pathology.

Conclusions: Analogous to human RP, the mouse genetic background strongly influences the rd1 phenotype. Thus, different rd1 mouse lines may follow different timelines of retinal degeneration, making exact knowledge of genetic background imperative in all studies that use rd1 models.

No MeSH data available.


Related in: MedlinePlus