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An Update on the Regulation of Rod Photoreceptor Development
Edward M. Levine and Sabine Fuhrmann
CONTENTS
INTRODUCTION
BRIEF OVERVIEW OF RETINAL DEVELOPMENT AND EARLY STAGES OF ROD
PHOTORECEPTOR DIFFERENTIATION
TRANSCRIPTION FACTORS
EXTRACELLULAR FACTORS AND SIGNAL TRANSDUCTION PATHWAYS
CONCLUSIONS AND FUTURE PROSPECTS
REFERENCES
INTRODUCTION
Photoreceptors are the most abundant retinal cells in all vertebrate species, and rods significantly outnumber cones in humans. Many retinal degenerative diseases arise due to perturbations in rod photoreceptor physiology or survival. Replacing dying photoreceptors by de novo production of new photoreceptors from a stem cell source is a strategy much sought after for treating these diseases. This approach in its essence requires our ability to manipulate stem cells and recapitulate the process of rod photoreceptor development. Another treatment strategy is to preserve existing photoreceptor function or survival by delivery of cytokines or growth factors to the diseased retina. In this case, we need to understand how the factors affect the photoreceptor cell (and other exposed cells as well). Since several of the factors being tested in clinical trials have key roles in photoreceptor development (and retinal development in general), our understanding of these processes is essential for evaluating the cause-and-effect relationships between the factors and the observed changes in treated photoreceptors.
In a review article published in 2000, we and our postdoctoral mentor, Dr. Thomas Reh, described what was known at the time regarding the importance of cellular interactions and the identities and roles of soluble factors in rod photoreceptor development [1]. In this chapter, we summarize the state of the field, with particular attention paid to the findings made since 2000 and with an emphasis on both cell-intrinsic and -extrinsic factors.
From: Ophthalmology Research: Visual Transduction and Non-Visual Light Perception
Edited by: J. Tombran-Tink and C. J. Barnstable © Humana Press, Totowa, NJ
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BRIEF OVERVIEW OF RETINAL DEVELOPMENT AND EARLY STAGES OF ROD PHOTORECEPTOR DIFFERENTIATION
To appreciate the complexity of photoreceptor differentiation, it is important to have a basic understanding of how the retina develops. Because of space limitations, we can only briefly outline the major points. However, there are many excellent reviews that consider retinal development from various perspectives, and listed here is a very limited sampling of what is available [2–8].
The seven neuroretinal cell classes all derive from a common pool of progenitor cells known as retinal progenitor cells (RPCs). RPCs are resident in the optic neuroepithelium and are produced as a result of patterning events that occur during optic vesicle formation. Early on, the RPCs proliferate extensively and soon after initiate neuroand gliogenesis. These processes, collectively termed retinal histogenesis, occur over significantly different developmental timescales among different vertebrate species, but certain key aspects of retinal histogenesis are remarkably well conserved. For example, there is a temporal progression in the production of cells in each class, and this order does not vary appreciably. Retinal ganglion cells, horizontal cells, and cone photoreceptors are born the earliest, followed by amacrine cells and rod photoreceptors; born last are the bipolar cells and Müller glia. As an example, Rapaport et al. [9] published an impressive quantitative analysis of retinal histogenesis in the rat. Cell marking-based lineage analyses revealed that as a population, RPCs are multipotential and lineage independent, meaning that these cells can produce more than one cell type, and their pattern of cell division is not deterministic with respect to cell output (although see [10] for a provocative contrast). An important issue then is to understand how the temporal order is established. Several now-classic cell culture and cell ablation experiments led to the model proposing that extracellular environmental factors are the primary driving forces behind retinal histogenesis and the regulation of its temporal progression. As a result, many extracellular signals and their signal transduction pathways are now known that influence histogenesis, and their precise functions and interactions are actively under investigation.
More recent studies showed that RPCs are not completely naïve, however. A modification of the above model states that the responsiveness of RPCs to signals changes as development proceeds, and that this is regulated by changes in gene expression. It is proposed that these changes influence the competence of RPCs to produce specific cells and to bias their output in a temporal and progressive manner. Thus, a more complete model of retinal histogenesis incorporates both cell-extrinsic and -intrinsic factors, and much effort is currently devoted to understanding how these factors are integrated into specific networks.
It is generally thought that cell-type-specific differentiation does not occur until the RPC exits the cell cycle. This is based in part on the outcomes of the lineage experiments (e.g., a single RPC division [two-cell clone]) can produce daughter cells with different fates) and on the collective observations that the expression of markers specific or deterministic for any single cell class or cell type is extremely rare in RPCs. Soon after RPCs exit the cell cycle, changes in cellular behavior and gene expression begin, and this continues until differentiation is complete. In the case of murine rod photoreceptors, this progression can last for over 2 weeks. Since the period of murine rod photoreceptor