Roof D J, Adamian M, Hayes A
Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston.
Invest Ophthalmol Vis Sci. 1994 Nov;35(12):4049-62.
To investigate the mechanism by which photoreceptors degenerate in transgenic mice carrying a mutant human rhodopsin gene (P23H).
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.
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.
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.
研究携带突变型人类视紫红质基因（P23H）的转基因小鼠中光感受器退化的机制。
使用视紫红质特异性抗体通过免疫细胞化学方法绘制由P23H视紫红质引起的视网膜退化的时间和空间模式。还确定了视紫红质、转导素和杆状细胞环鸟苷酸磷酸二酯酶（PDE）的亚细胞定位，并比较了P23H转基因小鼠、rd小鼠和皇家外科学院（RCS）大鼠之间的视紫红质定位。
在表达P23H视紫红质的转基因小鼠中，出生后第10天时中央的光感受器开始丧失。随着视网膜退化，视紫红质在外核层和光感受器突触终末内积累。P23H转基因视网膜在外网状层中也显示出转导素和PDE的积累。相比之下，所研究的其他类型的遗传性视网膜退化在外核层中显示出类似的视紫红质积累模式，但在视网膜的外网状层中则没有。
P23H转基因视网膜的退化模式与一种模型一致，即位于中央的、最先产生的光感受器最先死亡。与遗传性视网膜退化的其他动物模型（rd、RCS）不同，P23H退化的一个新特征是视紫红质、转导素和PDE在视网膜外网状层中的积累。解释这一观察结果的一种假设是，P23H视紫红质在细胞内通过正常视紫红质未使用的途径进行转运。通常与盘膜相关的外周转导蛋白的非突变形式，如转导素和PDE，可能会伴随异常转运的视紫红质。
