The retina is a thin nervous tissue that lines the back of the eye and is responsible for detecting and relaying light stimuli to the brain. The retina is made up of seven principal cell types arranged into three layers (Figure 1). These include rod and cone photoreceptors; amacrine, bipolar, and horizontal interneurons; retinal ganglion cells (RGCs); and Müller glia. Rod photoreceptors are very sensitive to light and are responsible for night vision. These are the most abundant cell type in the human retina and are located closest to the back of the eye, near the retinal pigmented epithelium (RPE). Cone photoreceptors are responsible for high acuity vision (like reading) and color discrimination. There are three types of cones in the human retina, each attuned to a specific wavelength of light (blue, green, red). Photoreceptors send their signals via bipolar interneurons. These signals are then relayed to the brain via RGCs. Horizontal and amacrine interneurons modulate signaling between photoreceptors, bipolars, and RGCs. Lastly, Müller glia maintain the retinal neurons and establish a blood-retinal barrier between the vasculature and the neurons. Each of these cell types is important for normal vision.
Other cell types are present in the retina as well. The retina is perfused by blood vessels which form three layers (plexi). Two of the vascular plexi are deep inside the retina and one is near the inner surface of the retina (Figure 1). These vessels are made up of vascular endothelial cells and mural cells. Retinal astrocytes coat the surface of the retina and form a blood-retinal barrier with the surface vasculature (Figure 1). Müller glia form a blood-retinal barrier with the deep plexi. On a per weight basis, the retina is the most metabolically active tissue in the body. Thus, the nourishment provided by the retinal vasculature is critical for normal vision. The retina is also populated with microglia, which act as phagocytes (eating cells) and are similar to macrophages of the immune system.
There are many diseases that affect the retina (Figure 2). These diseases can affect neurons directly or other structures in the eye such as the vasculature or the RPE. If the disease process causes the death of retinal neurons, permanent vision loss can occur since neurons are not replaced. For example, age-related macular degeneration (AMD) results in permanent loss of photoreceptors and significant visual impairment due to RPE and/or vascular alterations (Figure 2). In diabetic retinopathy, the retinal vasculature is affected and retinal neurons are progressively lost (Figure 2). Patients with glaucoma (Figure 2) permanently lose their RGCs and cannot relay photic information to the brain. Less commonly, there are diseases caused by defects in genes that control the development and/or function of specific populations of retinal neurons. For example, mutations in genes that control photoreceptor function cause retinitis pigmentosa or Leber’s congenital amaurosis; each of which result in progressive photoreceptor loss (Figure 2) (Dr. James Friedman). How can vision be restored to people who have permanently lost retinal neurons? The key lies in discovering how these cells develop.
The entire complement of retinal neurons is formed before we are born. The retina starts out as a population of progenitor cells (similar to stem cells). These progenitors are multipotent, that is they can become any of the seven principal cell types of the retina. Over time, these progenitors permanently exit the cell cycle (stop dividing) and differentiate (mature) into neurons and glia. Different cell types are formed at different times. For example RGCs are formed early and glia are formed late in development. While there is a trend to when each cell type is formed, there is considerable overlap such that multiple cell types are forming at any given time. How do these progenitors decide which type of cell to become (called “fate determination”)? Development is regulated by genetic programs that dictate a cell’s behavior. Cells are not alone, but communicate with each other, affecting the genetic programs of their neighbors. Thus, development is regulated within (intrinsic/autonomous) and between cells (extrinsic/non-autonomous). Discovering how these genetic programs are regulated can explain development. For example, knowing the molecular steps that drive the formation of cones may allow researchers to directly generate cone photoreceptors from stem cells, which could then be used to restore vision in patients with retinal disease.