Lin Bin, Masland Richard H, Strettoi Enrica
Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA.
Exp Eye Res. 2009 Mar;88(3):589-99. doi: 10.1016/j.exer.2008.11.022. Epub 2008 Dec 6.
We studied the survival of cone photoreceptors following the degeneration of rods in the rd mouse. Cones were visualized by selective expression of green fluorescent protein (GFP) following transduction with an adeno-associated virus (AAV) vector. As previously reported, many cones survive after the initial degeneration of the rods. Soon after the initial degeneration, they lose their outer segments and all but a vestigial inner segment; and they partially retract or lose their axon and synaptic pedicle. However, they retain many fundamental features of the cone phenotype, and for many weeks show a polarized morphology indicative of substantial regrowth of processes. The cells retain their laminar position, forming a cell row just distal to a much thinned outer plexiform layer. The somata subsequently enlarge. Most of the cells extend bipolar processes, recreating the original bipolar morphology of a photoreceptor cell--though now turned on its side relative to the native position. The cells express short- or middle-wavelength opsins, recoverin and connexin36. One or more of the polarized processes could often be shown to contain synaptic ribbons, as visualized by antibodies against RIBEYE. The cones do not express protein kinase C alpha, Go alpha, ChX10 or calbindin, markers of bipolar or horizontal cells. The partially differentiated cone morphology persists for at least several months, after which the processes begin to retract and there is slow loss of the cells. Thus, during the time following the loss of their rod-dominated microenvironment, the cones achieve a semi-stable state in which much of their normal phenotype is preserved. Cone photoreceptors in retinas of human RP donors appear from their morphology to undergo a similar progression. The therapeutic window for rescue of cone photoreceptors may be longer than would have been thought.
我们研究了rd小鼠视杆细胞退化后视锥光感受器的存活情况。通过腺相关病毒（AAV）载体转导后绿色荧光蛋白（GFP）的选择性表达来观察视锥细胞。如先前报道，许多视锥细胞在视杆细胞最初退化后存活下来。在最初退化后不久，它们失去外段以及除了残留的内段之外的所有部分；并且它们部分缩回或失去轴突和突触小足。然而，它们保留了视锥细胞表型的许多基本特征，并且在数周内呈现出极化形态，表明其突起有大量再生。这些细胞保持其层状位置，在变薄的外网状层的远侧形成一排细胞。随后细胞体增大。大多数细胞伸出双极突起，重新形成光感受器细胞原来的双极形态——尽管现在相对于原始位置发生了侧转。这些细胞表达短波长或中波长视蛋白、恢复蛋白和连接蛋白36。通过抗RIBEYE抗体可视化显示，一个或多个极化突起通常可显示含有突触小带。视锥细胞不表达蛋白激酶Cα、Goα、ChX10或钙结合蛋白，这些是双极细胞或水平细胞的标志物。部分分化的视锥细胞形态至少持续数月，之后突起开始缩回，细胞缓慢丢失。因此，在失去以视杆细胞为主的微环境后的这段时间里，视锥细胞达到一种半稳定状态，其中它们的许多正常表型得以保留。人类视网膜色素变性（RP）供体视网膜中的视锥光感受器从形态上看似乎经历了类似的过程。拯救视锥光感受器的治疗窗口可能比预期的更长。
