Rhodopsin accumulation at abnormal sites in retinas of mice with a human P23H rhodopsin transgene.

Abstract

PURPOSE:

To investigate the mechanism by which photoreceptors degenerate in transgenic mice carrying a mutant human rhodopsin gene (P23H).

METHODS:

The temporal and spatial pattern of the retinal degeneration caused by P23H rhodopsin was mapped using immunocytochemistry with rhodopsin-specific antibodies. The subcellular localizations of rhodopsin, transducin, and rod cGMP phosphodiesterase (PDE) were also determined, and rhodopsin localization was compared among P23H transgenic mice, rd mice, and Royal College of Surgeons (RCS) rats.

RESULTS:

In transgenic mice that express P23H rhodopsin, photoreceptors are lost centrally by postnatal day 10. As the retina degenerates, rhodopsin accumulates in the outer nuclear layer and within the photoreceptor synaptic terminals. The P23H transgenic retinas also show an accumulation of transducin and PDE within the outer plexiform layer. In contrast, other types of hereditary retinal degenerations studied show a similar pattern of rhodopsin accumulation in the outer nuclear layer but not in the outer plexiform layer of the retina.

CONCLUSIONS:

The pattern of degeneration in the P23H transgenic retina is consistent with a model in which the centrally located, first-born photoreceptors are the first to die. In contrast to other animal models for hereditary retinal degeneration (rd, RCS), a novel feature of the P23H degeneration is an accumulation of rhodopsin, transducin, and PDE within the outer plexiform layer of the retina. One hypothesis to explain this observation is that P23H rhodopsin is routed intracellularly through a pathway not used by normal rhodopsin. Nonmutant forms of the peripheral transducing proteins normally associated with disk membrane, such as transducin and PDE, may accompany the aberrantly routed rhodopsin.

• Authors: D J Roof, M Adamian, A Hayes
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 35 Issue 12 Pg. 4049-62 (Nov 1994) ISSN: 0146-0404 [Print] United States
• PMID: 7960587 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Rhodopsin
• 3',5'-Cyclic-GMP Phosphodiesterases
• Transducin

Topics

• 3',5'-Cyclic-GMP Phosphodiesterases (metabolism)
• Animals
• Fluorescent Antibody Technique
• Gene Expression
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Microscopy, Immunoelectron
• Photoreceptor Cells (metabolism, pathology)
• Retina (metabolism)
• Retinal Degeneration (genetics, metabolism, pathology)
• Rhodopsin (genetics, metabolism)
• Transducin (metabolism)