The neuroretina, an experimental system to probe multifacted biological
and disease processes
Figure 1. The mammalian neuroretina. Simplified representation of the mammalian retinal network comprising the well-stratified organization of photoreceptor subtypes [rods and red, green and blue cones (C)], second-order neurons [horizontal (H), bipolar (B) and amacrine (A) neurons] and ganglion neurons (G) whose axons extend to the brain, where they synapse to the other neurons. The retinal pigment epithelium (RPE) supports photoreceptor neurons and comprises part of the blood-brain barrier of the retina.
We use extensively, albeit not exclusively, the mammalian neuroretinal network (Figure 1) in our studies for several reasons. First, the retina, which lines the inner posterior chamber of the eye, provides a remarkable "window" to study the central nervous system and allied diseases. The neuroretina comprises neural and glial cells, whose cellular and subcellular architectures and functions are extremely diverse, yet relatively well defined, and very amenable to experimental examination and manipulation. This allows to probe with ease the role of fundamental biological processes, such as long- and short-range signaling and polarized intracellular trafficking, across diverse or closely related populations of neurons. Second, about one fifth of the human genes causing mendelian disease traits contribute to non-syndromic or syndromic vision diseases and they often affect selective retinal neurons, the retinal pigment epithelium (RPE) or both. For example, retinitis pigmentosa (RP) causes primarily the degeneration of rod photoreceptors and the secondary loss of cones photoreceptors, age-related macular degeneration (AMD) causes the degeneration of RPE and photoreceptor cells, and glaucoma and optic nerve neuropathies promote the degeneration or impairment of ganglion neurons. Further, some of these and other complex neurological diseases promote
the disintegration of neural networks through the autonomous and non-autonomous death of selective neurons or supporting cells by ill-defined mechanisms. Aging and other stressors act also as strong modifiers of disease onset, progression and expression. Third, the survival of distinct classes of neurons are often dependent on the relay of environmental cues to intracellular molecular and subcellular processes, many of which are still poorly understood. Deregulation of the processing of these cues often triggers disease states in selective retinal neurons. Finally, the outcomes of these studies permit to gain novel insights into signaling and trafficking pathways and integration of these between retinal neurons and other neuronal and non-neuronal systems sharing homologous components, molecular frameworks or disease pathomechanisms.
Currently, our laboratory is employing two multifunctional and dynamic protein complexes assembled by multimodular proteins to investigate signaling and intracellular trafficking pathways, proteostasis and cross-talks between these in health and disease processes affecting selectively neural and other cell types. These scaffold proteins comprise the Ran-binding protein 2 (RanBP2) and the Retinitis Pigmentosa GTPase Regulator-Interacting Protein 1 (RPGRIP1).
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